General Guidelines for Clinical Evaluation of Ayurvedic Interventions

GUIDELINES SERIES-III

GENERAL GUIDELINES FOR CLINICAL EVALUATION OF AYURVEDIC INTERVENTIONS

CENTRAL COUNCIL FOR RESEARCH IN AYURVEDIC SCIENCES Ministry of AYUSH, Government of India New Delhi

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GENERAL GUIDELINES FOR CLINICAL EVALUATION OF AYURVEDIC INTERVENTIONS

Volume - III

CENTRAL COUNCIL FOR RESEARCH IN AYURVEDIC SCIENCES Ministry of AYUSH, Government of India New Delhi

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First Edition - 2018

Publisher: Central Council for Research in Ayurvedic Sciences, Ministry of AYUSH, Government of India, New Delhi, J. L. N. B. C. A. H. Anusandhan Bhavan, 61-65, Institutional Area, Opp. D-Block, Janakpuri, New Delhi - 110 058, E-mail: [email protected], Website : www.ccras.nic.in

Disclaimer: All possible efforts have been made to ensure the correctness of the contents. However Central Council for Research in Ayurvedic Sciences, Ministry of AYUSH, shall not be accountable for any inadvertent error in the content. Corrective measures shall be taken up once such errors are brought to notice.

ISBN : 978-93-83864-22-5

Other Related Guidelines: Volume-I: General Guidelines for Drug Development of Ayurvedic Formulations Volume - II: General Guidelines for Safety/Toxicity Evaluation of Ayurvedic Formulations

Printed a t: JK Offset Graphics Pvt. Ltd., New Delhi-110020

PROLOGUE

Research and Development in the field of AYUSH system in different areas such as drug development including quality assurance, pre-clinical safety evaluation and Clinical Research are being conducted at different levels such as Research Council under AYUSH, Academic institutions (both AYUSH and non AYUSH institutes such as Medical Colleges, Universities etc.), other Research organizations such as ICMR, CSIR etc. Further, research support is also being extended through grant under Extra Mural Research (EMR) vide Ministry of AYUSH, DST, DBT, ICMR etc. in the area of traditional medicine.

Lot of research is being conducted at different levels as above in the field of AYUSH adopting different guidelines, methods and protocols and ending up research outcomes with low or poor translational value. Only few of them have led to clinical trial and marketing level. This may be attributed to lack of awareness regarding AYUSH strategies for R&D and provisions of Drug & Cosmetic Act related to AYUSH.

In spite of availability of several guidelines such as GCP guidelines for ASU drugs, ICMR Guidelines for Bio medical Research for Human Participants, GCP Guidelines published by CDSCO Ministry of Health and Family Welfare, WHO guidelines for traditional medical research and GCP guidelines for ASU drugs published by Ministry of AYUSH, there is no single comprehensive directive to conduct research in AYUSH sector is available.

This might be one among the major reasons that has led to Research and Development in AYUSH sector with diverse approaches with low translational value.

In view of this, it becomes imperative to develop directives on research practices for various components of AYUSH research sectors for uniform adoption across all stake holders such as research councils, academic institutes, funding agencies engaged in AYUSH research.

Considering this, efforts have been made by CCRAS and developed three comprehensive and concise Guidelines focusing on drug development (Standardization and quality assurance), safety and toxicity and clinical evaluation for ready reference of stakeholders. These Guidelines encompassed with research practices may be suitably adopted and followed by investigators in the field of Ayurveda system such as Research organizations, academic institutions and Investigators seeking grant from schemes of different agencies funding for research on AYUSH system, would certainly help the investigators while designing and formulating the proposals and also planning academic industrial research in the field of AYUSH systems. The users may refer other two documents for having an overall idea concerning drug development and R & D in this field.

GLOSSARY

S.No. Terms with definitions 1. Accountability The obligation of an individual or organization to account for its activities, accept responsibility for them, and to disclose the results in a transparent manner. 2. Act Wherever relevant, the Act means Drugs & Cosmetics Act 1940 (23 of 1940) and the Rulesmade thereunder. 3. Adverse Drug All noxious and unintended responses to a medicinal product related reactions to any dose used in human for the prophylaxis, diagnosis, or therapy (ADR) of disease, or for the modifications of physiological function. ADRs are classified into six types: dose-related (augmented), non-dose- related (Bizarre), dose-related and time-related (Chronic), time- related (delayed) withdrawal (end of use) and failure of therapy (failure). 4. Adverse event Any untoward medical occurrence in a participant or clinical investigation participate administered an investigational product and which does not necessarily have a casual relationship with this treatment. The adverse event can therefore be any unfavorable or unintended sign or experience associated with the use of the investigational product, whether or not related to the product. 5. Assent To agree or approve after thoughtful consideration of an idea or suggestion. In these guidelines it means agreement or approval mostly in children > 8 years of age, which has to be corroborated with informed consent of legally authorized representative (LAR). 6. Assessment An official record of the review decision along with comments and form dated signature of the reviewer. 7. Audit A systematic and independent examination of trial activities and documents to determine whether the review and approval activities were conducted and data were recorded and accurately reported according to the study protocol, SOPs, GCP, Declaration of Helsinki and applicable guidelines and regulatory requirements. 8. Authority Authority means the Biomedical and Health Research Authority established under an Act. 9. Autonomy It is the ability and capacity of a rational individual to make an independently informed decision to volunteer as a research participant. 10. Ayurvedic drug Includes all medicines intended for internal or external use for or in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, and manufactured exclusively in accordance with the formulae described in the authoritative texts of ayurvedic system of medicine and Ayurvedic pharmacopeia of India specified in the first schedule of the Drugs & cosmetics Act 1940, Rules, 1945. These are also called as classical drugs which are manufactured and named in accordance with the formulations described in the authoritative texts. 11. Ayurveda Includes any existing/ new intervention with drug, therapeutic intervention regimens (Panchakarma and lifestyle advocacy, etc.), or parasurgical (Agnikarma, leech application, Ksharasutra, etc.) or surgical procedure or device in Ayurveda.

12. Behavioral Refers to studies of the behaviour of individuals, or groups, or Research organizations or societies. 13. Biomedical and Includes basic, applied and operational research designed primarily to Health increase the scientific knowledge about diseases and conditions Research (physical or socio-behavioral), their detection, cause and strategies for health promotion or amelioration of disease and rehabilitation and includes clinical research. 14. Blinding / A method of “control experimentation” in which one or more parties Masking involved are not informed of the treatment being given. Single blind refers to the study subject(s) being unaware, while Double blind refers to the study subject(s) and/or investigators), monitor, data analyst(s) are being unaware of the treatment assigned. 15. Blinded studies A blind or blinded study is an experiment in which information about the test is masked (kept) from the participant, to reduce or eliminate bias, until after a trial outcome is known. Double blinded means even the investigator does not know which is the test intervention. 16. Case control A study that compares participants who have a disease or outcome of studies interest (cases) with participants who do not have the diseases or outcome (controls), and looks back retrospectively to compare frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease. 17. Case report Case record form or case report form is printed, optical or electronic form (CRF) document designed to record all of the protocol required information to be reported to the sponsor on each trial participant. 18. Case series A case series (also known as a clinical series) is a type of medical research that tracks participants with a known exposure, e.g., participant who have received a similar treatment or examines their medical records for exposure and outcome. 19. Clinical trials registry- India A clinical trials registry is an official platform for registering a trial (CTRI) involving human participants in India. 20. Clinical trial A clinical trial is any systematic research / study that prospectively assign human participants or groups of humans to one or more health- related intervention/s to evaluation the safety and efficacy. 21. Confidentiality Maintenance of privacy of study subjects including their personal identity and all medical information, from individuals other than those prescribed in the Protocol. Confidentiality also covers the prevention of disclosure of sponsor’s proprietary information to unauthorised persons. 22. Co-Investigator A person legally qualified to be an investigator, to whom the Investigator delegates a part of his responsibilities. 23. Data and Safety The Data and Safety Monitoring Board (DSMB) is a board, charged Monitoring with monitoring the accumulating data from a Board pharmacotherapeuticclinical trial to detect and report early evidence of prespecified or unanticipated benefit or harm to trial participants that may be attributable to one of the treatments under evaluation. The DSMB will conduct an independent, objective review of all

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accumulated data from both blinded and unblended clinical trials in such a manner as to maximize benefit to the trial participants and to the research effort. 24. Documentation All records (including written documents, electronic, magnetic or optical records, scans, x-rays etc.) that describe or record the methods, conduct and results of the study, and the actions taken. The Documents include Protocol, copies of submissions and approvals from the relevant regulatory authority (if required), ethics committee, investigator(s)’ particulars, consent forms, monitor reports, audit certificates, relevant letters, reference ranges, raw data, completed CRFs and the final report. Also see: Essential Documents 25. Essential The Documents that permit evaluation of the conduct of a study and Documents the quality of the data generated. 26. Ethics An independent review board or committee comprising of medical / Committee scientific and nonmedical / non-scientific members, whose responsibility is to verify the protection of the rights, safety and well being of human subjects involved in a study. The independent review provides public reassurance by objectively, independently and impartially reviewing and approving the “Protocol”, the suitability of the investigators), facilities, methods and material to be used for obtaining and documenting “Informed Consent” of the study subjects and adequacy of confidentiality safeguards. 27. Final Report A complete and comprehensive description of the study after its completion. It includes description of experimental and statistical methods and materials, presentation and evaluation of the results, statistical analyses and a critical ethical, statistical and clinical appraisal. The Investigator’s declaration closing the study is a part of the Final Report. 28. Good Clinical It is a standard for clinical studies or trials that encompasses the Practice (GCP) design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies. It ensures that the studies are implemented and reported in such a manner that there is public assurance that the data are credible, accurate and that the rights, integrity and confidentiality of the subjects are protected. GCP aims to ensure that the studies arescientifically authentic and that the clinical properties of the “Investigational Product” are properly documented. 29. Informed Voluntary written consent of a subject’s willingness to participate in a Consent particular study and in its documentation. The confirmation is sought only after information about the trial including an explanation of its status as research, its objectives, potential benefits, risks and inconveniences, alternative treatment that may be available and of the subject’s rights and responsibilities has been provided to the potential subject. 30. Institution Any public or private medical facility where a clinical study is conducted. 31. Investigator A person responsible for the conduct of the study at the trial site.

Investigator is responsible for the rights, health and welfare of the study subjects. In case the study is conducted by a team of investigators at the study site then the designated leader of the team should be the Principal Investigator. Also see Principal Investigator, Sub-investigator. 32. Monitor A person appointed by the Sponsor or Contract Research Organisation (CRO) for monitoring and reporting the progress of the trial and for verification of data. The monitor ensures that the trial is conducted, recorded and reported in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory requirements. 33. Multicenter A clinical trial conducted according to one single protocol in which Study the trial is taking place at different investigational sites, therefore carried out by more than one investigator. 34. Non-Clinical Biomedical studies that are not performed on human subjects. Study 35. Non- A study in which there is no anticipated direct clinical benefit to the Therapeutic Subjects). Such studies, unless an exception is justified, should be Study conducted in patient(s) having a disease or condition for which the Investigational Product is intended. Subject(s) in these studies should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed. 36. Pharmaceutical Any substance or combination of substances which has a therapeutic, Product(s) prophylactic or diagnostic purpose or is intended to modify physiological functions, and presented in a dosage form suitable for administration to humans. 37. Patent or In relation to Ayurvedic, Siddha or UnaniTibb systems of medicine, Proprietary all formulations containing only such ingredients mentioned in the Medicine formulae described in the authoritative books of Ayurveda, Siddha or UnaniTibb system of medicine specified in the firstSchedule, but does not include a medicine which is administered by parenteral route and also a formulation included in the authoritative books as specified in clause (a)of Drugs & cosmetics Act, 1940 and rules 1945. 38. Protocol A document that states the background, objectives, rationale, design, methodology (including the methods for dealing with AEs, withdrawals etc.) and statistical considerations of the study. It also states the conditions under which the study shall be performed and managed. A list of items to be included in the Protocol is compiled in a subsequent chapter. The content and format of the protocol should take into consideration the adopted SoPs, the regulatory requirements and the guiding principles of GCP. The term Protocol, unless otherwise specified, relates to the latest amended version of the document, read in conjunction with all its appendices and enclosures 39. Protocol Any changes or formal clarifications appended to the protocol. All

Amendments) Protocol Amendments should be agreed upon and signed by the persons who were the signatories to the Protocol. 40. Quality Systems and processes established to ensure that the trial is performed Assurance and the data are generated in compliance with GCP. QA is validated (QA) through in-process Quality Control and in and post-process auditing of clinical trial process as well as data. 41. Quality Control The operational techniques and activities undertaken within the (QC) system of QA to verify that the requirements for quality of the trial related activities have been fulfilled. QC activities concern everybody involved with planning, conducting, monitoring, evaluating, data handling and reporting. The objective of QC is to avoid exposure of study subjects to unnecessary risks and to avoid false conclusions being drawn from unreliable data. 42. Randomisation The process of assigning study subjects to either the treatment or the control group.Randomisation gives all subjects the same chance of being in either group in order to reduce bias. 43. Raw Data It refers to all records or certified copies of the original clinical and laboratory findings or other activities in a clinical study necessary for the reconstruction and evaluation of the trial. Also see source data. 44. Rescue A supplementary treatment to relieve the trial subject of the Medicine symptoms caused by the investigated disease in a study, usually given to alleviate pain in placebo-controlled trials. 45. Serious An AE or ADR that is associated with death, inpatient hospitalisation Adverse Event (in case the study was being conducted on out-patients), prolongation (SAE) or of hospitalisation (in case the study was being conducted on in Serious patients), persistent or significant disability or incapacity, a congenital Adverse Drug anomaly or birth defect, or is otherwise life threatening. Reaction (SADR) 46. Source Data Original documents (or their verified and certified copies) necessary for evaluation of the Clinical Trial. These documents may include Study Subjects’ files, recordings from automated instruments, tracings, X-Ray and other films, laboratory notes, photographic negatives, magnetic media, hospital records, clinical and office charts, Subjects’ diaries, evaluation check-lists, and pharmacy dispensing records. 47. Sponsor An individual or a company or an institution that takes the responsibility for the initiation, management and / or financing of a Clinical Study. An Investigator who independently initiates and takes full responsibility for a trial automatically assumes the role of a Sponsor. 48. Study Product Any Ayurvedic drug / Patent or Proprietary Medicines / therapies or comparator product used in a clinical study

Background

Quests for healthy and long life are perhaps as old as human existence and efforts are unremitting to address the challenges and triumph over the bottlenecks across this journey. Ayurveda-the science of life, evolved as a comprehensive system of healthcare systematically through scientific experimentations of high order backed by sound and reproducible evidence base and stood the test of the time. Several strategies and road maps are being drawn to carry forward merits of this science so as to meet the current day health needs and mainstream its core strengths alongside through research & development in this country and across the globe.

The fundamental aspects of holistic systems need adequate positioning, while designing clinical trials to examine the safety and efficacy of Ayurveda approaches. Furthermore, the other challenges and issues related to quality and safety viz. dosage forms/delivery system, diverse concepts and complex approaches in trial design, diagnosis and therapy, outcomes of clinical efficacy and drug interactions also pose certain limitations in research. A holistic approach may be adopted to validate the therapies and approaches with integration of principles of Ayurveda and bio-medicine without losing the vital fundamentals of both systems. Such an approach with well designed research plans could possibly facilitate to generate tangible evidence.

The areas of clinical research broadly comprise validation of the fundamental principles of Ayurveda; Validation and development of diagnostic/assessment tools ; standardization and validation of the therapy/ procedures; to establish dosage form, dose, duration, indication of any given drug as per the classics and to develop new regimen.

The expertise and experience of the investigators, all the equipments and infrastructure, trial drugs, necessary diagnostic methods and availability of participants according to the requirements of research question should be examined carefully and thoroughly to achieve the outcomes (Upaya).

A critical review of Ayurvedic literature reveals the reflection of epistemology of Ayurveda and its robust approach towards Research & Development. The methodical approaches adopted from Darshanas (Doctrines of Philosophy) form the basis of research tools for generation of evidence and development of classical Ayurvedic texts i.e. Samhitas. They comprise the following-

• Aptopadesa (Evidence base on therapeutic leads) • Pratyaksha (Direct evidence) • Anumana (Logical inference) • Upamana (Analogy: Comparative /Control design) • Yukti (Reproducible Experimental Evidence)

The two way approach of experimentation and drug trials as mentioned in Samhitas forms the roots of clinical trial. As such, Sushruta Samhita narrated the methods and approaches viz. feasibility of test intervention (Tatlingatwat), observational design (Dristaphalatwat), System validation (Agamaatsya), for testing an intervention and interpretation of observations in the context of Kriyakala (stages of etiopathogenesis of a disease) which reflect the reverse pharmacology or reverse renovation approach of contemporary period. This could be well utilized as fast screening method of test interventions.

Further, Maharshi Charak's approach emphasizes on meticulous design and reproducibility. This comprise the issues such as Feasible ideology / Hypothesis (Budhipashyati-ya-bhavaan), multi dimensional approach in planning and assessment (Bahukaranayogajaari), appropriate design (Yukti-Yojna) perpetually valid outcome and reproducibility (Yuktihtrikalah).

The concepts and methods are developed in course of time adding several new drugs, interventions and approaches right from Vedic period, Samhita period, medieval period and current era enriching the Ayurvedic pharmacopoeia and pharmaco-therapeutics.The evolution of Ayurvedic Pharmacopeia is depicted in Table 1.

Table 1: Evaluation of Ayurvedic pharmacopoeia

Period Plants Remarks on changes Literature

3000 BC - 289 Building a Pharmacopoeia Vedic texts 1000 BC (Atharvaveda) 1500 BC - 650 Incorporation/discarding drugs Ayurvedic Texts 500 AD • Charaka Samhita Sushrut Samhita • AstangaSamgraha

500 AD- 2000 Incorporation/discarding drugs 16 major Nighantus 1900 AD Varieties identified (like Dhanvantri Substitutes identified Nighantu, Bhavprakash Expansion in applications Nighantu, Raj Nighantu upto Shaligram Nighantu)

In light of the above it is essential to adopt an interdisciplinary approach for validation of Ayurvedic drugs and therapies without losing core fundamentals of Ayurveda. The suggested model is in Figure 1.

Disease/Participant Classification i r ] Diagnosis based on Modem Ayurvedic Principles Prakrti, Methods Dosha, Dushya etc. Therapeutic classification of Drugs i r Conventional Ayurvedic t j i Stage I - Controlled Clinical Observations 1 r Combined Results Conventional Analysis based on Ayurvedic Principles Stage II 1

Expanded Therapeutic Use Mechanism of Action (Traditional: Modem)

Figure 1: Evidence Base in Ayurveda: Suggested Approach

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(preparation of preclinical dossier) preclinical of (preparation (based on available guidelines guidelines available on (based methodology.) classical and ^ (6) correlation clinical for action of mechanism Pharmacogonostic/Chemical studies of studies Pharmacogonostic/Chemical (3) ingredients. Botanical identification/ Botanical with IAEC approval. IAEC with Animal Studies for biological activity and /or and activity biological for Studies Animal

Data analysis Data Trial conduct and monitoring and conduct Trial Collection of Collection (2) drugs raw current (considering practices agricultural good practices collection field good ^ methods) textual classical and studies (acute/sub-acute/chronic use therapeutic intended per as with approval of IEC/IRB and CTRI registration CTRI and IEC/IRB of approval with DRUG DEVELOPMENT PHASES (2-8)PREPARATORY PHASE (1) PHASE (2-8)PREPARATORY PHASES DEVELOPMENT DRUG with IAEC approval) IAEC with Pre clinical safety studies (5) studies safety clinical Pre

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General Methodologies Guidelines& ofDrug Development

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Figure 3: Scheme for Research on herbal medicines

Figure-4: Suggested approach for the inchision of “Folklore” herbal medicines in modern Pharmacopoeia

INDEX

Contents Page No. Prologue iii Glossary iv Background ix General methodologies & guidelines of drug development xii 1. CLINICAL RESEARCH PROTOCOL AT A GLANCE 1 2. PRE-REQUISITE FOR CLINICAL RESEARCH 1-28 2.1 Intervention Details 1 2.1.1 Drug 1 2.1.2 Therapy/ Procedure 2 2.1.2.1 Panchakarma procedure 2 2.1.2.2 Para surgical procedure 3 2.2 Data on Pilot/Preliminary Study 4 2.3 Study Protocol 4 2.3.1 General Information 4 2.3.2 Background Information and Scientific Rationale 5 2.3.2.1 Research question/Hypothesis (Pratisthapana) 5 2.3.2.2 Description and justification for the population to be studied 5 2.3.2.3 Interventions (if applicable) 5 2.3.2.4 Potential Risks 5 2.3.2.5 Potential Benefits 6 2.4 Study objective 6 2.5. Study Outcomes 6 2.5.1 Primary Outcome Measure 6 2.5.2 Secondary Outcome Measures 7 2.6. Study Design 7 2.6.1. Phases of clinical trial for Ayurveda drug/Patent or 8 Proprietary Medicines 2.6.1.1 Human Pharmacology (Phase I) 8 2.6.1.2 Therapeutic exploratory trials (Phase II) 8 2.6.1.3 Therapeutic confirmatory trials (Phase III) 9 2.6.1.4 Post Marketing Trials (Phase IV) 10

2.6.2. Types of the clinical study 10 2.6.2.1 Observational Study 11 2.6.2.2 Experimental Study 12 2.6.2.3 Data Based Studies 16 2.7. Randomization 17 2.7.1. Randomization Method and Procedure 17 2.7.2. Methods of Blinding 18 2.7.3. Randomization codes and Procedures for Breaking the Code 18 2.8. Study of Period 20 2.8.1. Total duration of the study 20 2.8.2. Timelines with deliverables 20 2.9. Sample Size Considerations 21 2.10. Participant Enrolment and Withdrawal 21 2.10.1. Participant Inclusion Criteria 21 2.10.2 Participant Exclusion Criteria 21 2.10.3 Withdrawal Criteria 22 2.11. Study Procedures 23 2.11.1 Screening 23 2.11.2 Enrollment/Baseline visit 23 2.11.3 Follow-up visit 23 2.11.4 Final Study Visit 23 2.11.5 Re-scheduled Visit -if any 23 2.11.6 Early Termination Visit-if any 23 2.11.7 Laboratory Evaluations 23 2.11.8 Efficacy evaluation(Assessment criteria) 24 2.11.9 Assessment of safety 24 2.11.9.1 Adverse Reactions / Adverse Events 24 2.11.9.2. Serious Adverse Events 24 2.12. Rescue Medication 25 2.13. Concomitant Medication 25 2.14. Statistical Analysis 25 2.15. Criteria for the discontinuation of the study and Termination 26 of the study 2.16. Project Monitoring & Auditing and Data Safety Monitoring 27 Board (DSMB)

3. ETHICS AND SAFETY CONSIDERATION 28-44 3.1. Ethical Principles 28 3.2. Ethics Committee 30 3.2.1 Basic Responsibilities 30 3.2.2 Composition of IEC 30 3.2.3 Terms of Reference for IECs 31 3.2.4 Review Procedures 32 3.2.5 Submission of Applications 32 3.2.6 Decision making process 33 3.2.7 Interim Review 34 3.2.8 Record keeping 34 3.2.9 Special considerations 35 3.3. Informed Consent process 35 3.3.1 Patient/ Participants Information Sheet 36 3.3.2 Informed Consent form 36 3.3.2.1 Informed Consent of Participants 36 3.3.2.2 Informed consent in Non-Therapeutic Study 37 3.3.2.3 Community consent 38 3.3.2.4 Documentation of Informed Consent process 38 3.3.2.5 Procedures after the consent process 39 3.4. Waiver of Consent 39 3.5. Responsibilities of the Researcher 39 3.6. Responsibilities of the Institution for conducting a research in 41 alliance with industries/commercial companies 3.7. Selection of Vulnerable groups as Research Participant 41 3.7.1 Pregnant or nursing women: 42 3.7.2. Children 43 4. REGISTRATION OF CLINICAL TRAIL (CTRI) 44 5. RECORD KEEPING AND DATA HANDLING 45-46 5.1 Documentation 45 5.2 Corrections 45 5.3. Electronic Data Processing 45 5.4. Validation of Electronic Data Processing Systems 46 5.5. Language 46

5.6. Responsibilities and the Investigator 46 5.7. Responsibilities of the Sponsor and the Monitor 46 6.PUBLICATION POLICY 47 7. COMMON PROBLEMS IN DEVELOPING RESEARCH 47 PROTOCOLS 8. FINAL STEPS 47 9.REFERENCES 48-49 10. FURTHER READING MATERIAL 50 -5 1 11. ANNEXURES 52-97 Annexure-I-158(B) Guidelines For Issue of License With Respect To 52 Ayurveda, Siddha or Unani Drugs Annexure -II Gazette Notification For Phytopharmaceutical Drugs 55 Annexure -III Levels of evidence 65 Annexure- IV Template for Monitoring 66 Annexure-V Data and Safety Monitoring Board (DSMB) Guidelines 68 Annexure-VI List of SoPs 72 Annexure-VII Essential document for the conduct of a clinical trial 73 Annexure-VIII Investigators Brochure 81 Annexure- IX Ayurveda Case Format 83 Annexure-X Experts Involved in Development of Guidelines and 97 Consultative Process

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1. Clinical Research protocol at a Glance (Limit to 1-2 pages)

Title: Include title o f the study with type o f trial (e.g., dose-ranging, observational, double-blind, etc.) Objectives: Include study objectives Primary: Secondary: Outcome measures Include primary/secondary outcome measures and method by which outcome will be determined. Primary: Secondary: Population: Include sample size, gender, age, general health status, geographic location, etc Phase: Mention the phase o f the study (I, II, III, IV) Number of Sites: Single/ Multi-centre Study Design: Open label, Randomized, Masking etc. Study Duration: Provide time from when the study initiation and until the study completion with close out. . Participant’s participation Provide time it will take to conduct the study for each individual Duration: participant. Description of study Include name o f the intervention alongwith reference, dose, intervention: dosage form, Anupana (vehicle), route o f administration and references along with the name o f the intervention Estimated time to complete Provide estimated time from enrollment into study of the first the enrollment participant to enrollment into study o f the last participant. Utility of the study outcome

2. Pre-Requisite for Clinical Research

2.1. Intervention Details

2.1.1. Drug a. Quality assurance & standardization of the trial drugs

The standardized drugs (as per pharmacopoeial standard/ in house standard) should be

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taken for the trial. The physical characteristics along with passport data of raw drugs, standard operating procedures for preparation, certification of analysis of both raw materials and finished product should be properly documented. {For this purpose, the guidelines for quality assurance, CCRAS 2018 can be referred). b. Safety/ toxicity studies & Biological actMtyiFor this purpose, the guidelines and directives for safety/toxicity o f Ayurvedic interventions, CCRAS 2018 can be referred.

2.1.2. Therapy/ Procedure Following factors may be considered while designing efficacy studies/validation of the therapy or procedures

General consideration for Panchakarma/other Procedures

Suitable, unsuitable persons for the therapy/procedures/diseases Pre and post therapeutic procedures Ideal season/periods Possible errors by the performers/participant and their prevention Duration of each procedure based on individual constitution/severity of disease condition Possible complications/adverse events and their management Dietary life style guidelines before, during and after performing Therapy/Procedures Quality of medicine Subjective and objective parameters of evaluation

2.I.2.I. Panchakarma procedures (Please refer Guidelines on basic training and safety in Panchakarma-czvaz7a6/e at CCRAS Website) i. Poorvakarma (Preparatory procedures') Deepana^Appetize^J^achana (Digestive) ,Snehana (internal/external use of oil/ghee) and Swedana (Medicated sudation) • Source of procurement of trial drug • SoPs for the preparation of drug(s) • Dose and Dosage form • Route of administration • Time of administration • Duration ii. Pradhankarma (Main Procedures)

Vaman &zrma(Therapeutic Emesis), Virechan Karma (Therapeutic purgation), Anuvasan

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5a5ri(Oil/Unctuous Enema), Asthapana Basti (Decoction based enema) and Nasya Karma(Nasal administration of medicaments) • Source of procurement of trial drug(s) • SoPs for the preparation • Dose and Dosage form • Route of administration • Time of administration • Duration • vehicle along with justification (classical/published data) • End Point of the Procedure( Samyak lakshan) iii. Paschatkarma (Post Therapy Procedures) • Specific paschatkarma according to pradhan karma • Samsarjana karma (Special Dietary regimen) with duration • Pathya-apathya (Diet and Life style) > Assessment of Participant compliance with study Intervention > Procedure for monitoring the participant compliance to therapy > Protocol for any other procedures like Shirodhara, Shirobasti, Janubasti, Uttara basti ,,Janudhara, Katibasti, Tarpana, Vidalaka, etc. may be designed as per above said panchakarma guidelines iv. Samsarjana karma (Special Dietary regimen) with duration After pradhan karma, digestion power diminishes, hence as per Ayurvedic principles researcher should advise the participants to take diet in a specific manner gradually increasing from liquids to semisolids and then to solid materials in a specific time according to the Pravara/madhyama/ avara shudhhi (Detoxification) achieved in the procedure. Special diet can be given in the meal timings (Twice/day) which start after Pradhan karma from the evening of that day. . It may last for 7 days in Pravara, 5 days in Madhyama and 3 days in Avara Shuddhi. Later, the person may be allowed to take normal diet.

2.I.2.2. Parasurgical Procedures i. Ksharasutra • Description of material and method • Source of procurement if any • SOPs for Preparation

General Guidelines for Clinical Evaluation of Ayurvedic Interventions • Time of administration • Duration • Pre and post-operative procedures ii. Agni karma • Description of material and method • Time of administration • Duration • Pre and post operative procedures iii. Rakta Mokshana • Description of material and method • Time of administration • Duration • Pre and post operative procedures • Samyaka Lakshana

2.2. Data on pilot/preliminary study (If applicable) Data on pilot study is essential in order to evaluate the feasibility, time, cost, adverse events, and effect size (statistical variability) for calculating the appropriate sample size and the study design prior to plan a clinical trial.

2.3. Study Protocol Study protocol is the plan of the study to attempt or achieve the research question. It is the vision of an Investigator by which the work is carried out to accomplish.

2.3.1. General Information • Protocol title, protocol identifying number and date. All amendments should bear amendment number and date(s) • Name, address & contact details of the sponsor and the monitor / CRO • Name and designation of the persons authorised to sign the protocol and the protocol amendments for the sponsor. • Name, title, address and contact details of the sponsor’s medical expert for the study • Name(s), title(s), address(es) and details of the investigator(s) who is / are responsible for conducting the study, along with their consent letter(s)

• Name(s), address(es) and details of the institution(s) - clinical laboratories and / or other medical and technical departments along with the particulars of the head(s) of the institution(s) and the relevant department(s)

2.3.2. Background information and Scientific Rationale

This section should address background of both research question and/or interventions

2.3.2.1. Research question/Hypothesis (Pratisthapana) The description of the importance of the selected disease/condition in the context of current scenario should be presented appropriately i.e.existing disease prevalence, burden and do not have sufficient information to answer a question; there is a gap in the result of previous study(s) or the results or explanation of several investigators disagree with each other’s or desire for an innovation; review and discussion o f important literature and data that are relevant to the trial- to know whether others have investigated similar/ variables/ parameters/ methods/ results/ populations or geographic regions, etc. to avoid replication. It will provide the background in the context o f the study.

2.3.2.2. Description and justification for the population to be studied The justification for the population to be taken should be described in detail.

2.3.2.3. Interventions (if applicable) The name and description of the study intervention/investigational products(s)/ therapy along with references; Justification for the selection of the interventions along with the route of administration, dosage, dosing regimen, intervention periods, or behavioral intervention methods; findings/ leads from previous clinical studies; findings of the pre-clinical studies (in vitro or in vivo) that potentially have clinical significance, etc. should be in detail.

2.3.2.4. Potential Risks The relevant literature or other sources of information with reference may be reviewed for any potential risks of the study/interventions to human participants and should be provided in the background. Any risk reported in the pre-clinical study must also be provided .Further, if the Principal Investigator (PI) predicts any other risks to human participants should be addressed in the background.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 2.3.2.5. Potential Benefits The potential benefits in terms of physical, psychological, social, legal, economic, or any other benefits (payment to the participant if any, is not considered) to the human participants Should be mentioned. Further, if Investigator predicts any other benefit that may also be recorded.

2.4. Study Objective An objective is the reason for performing the study i.e. to find answer of the research question by the analysis of data collected during the study. The objectives of a study should be clearly specified from the beginning as it forms the basis for study design. These typically include: • Statement of purpose, e.g., to assess, to determine, to compare, to evaluate • General purpose, e.g., efficacy, safety, health seeking trends, epidemiological studies • Specific purpose, e.g., dose-response, superiority to placebo, non-inferiority to current standard of care. • Name(s) of intervention (e.g., procedure, drug, behavioral intervention) being evaluated, specification of doses or dose ranges to be studied, dose regimens etc.

A clinical study mainly has a primary or core objective. Other additional objectives, if any, are called secondary objectives. For example- If in a study, the effect of Medohara Guggulu on Sthaulya (obesity) is to be assessed then the primary objective may be written as “To assess the effect of Medohara Guggulu on weight loss/ Sthaulya (obesity) and if the clinical safety/improvement in the quality of life or increase in work efficiency, etc. have to be assessed, then these maybe treated as secondary objectives.

2.5. Study Outcomes An outcome is an observation variable or changes recorded in the study at one or more time points from the baseline after enrollment of the participant in the study. It is the end point or measurements required in line o f the objectives.

2.5.1. Primary Outcome Measures The end point of the primary objective is called primary outcome measure. Generally, there should be just one primary variable, with evidence that it will provide a clinically relevant, valid, and reliable measure of the primary objective (e.g., laboratory procedures, changes in the signs & symptoms, safety assays, etc).

2.5.2. Secondary Outcome Measures The endpoints of additional or secondary objectives are called secondary outcome measures. But any other results found at the time of data analysis and interpretation of study results are also the secondary outcome measures. Secondary outcome measures should be included, whether or not they add information about the primary objective or address secondary objectives. Discuss their importance and role in the analysis and interpretation of study results. For example- I f in a study, the effect o f Medohara Guggulu on Sthaulya (obesity) is to be assessed and the primary objective is weight loss, then “To see the changes in the weight from the baseline at the end o f 1st or 2nd or 3rd months o f the treatment” [according to the interval (continuous, binary, event times) when the expected changes by the effect o f the intervention to be observed] "will be the primary outcome measure. Changes in the lipid profile, changes in the quality o f life, etc. may be considered as the secondary outcome measure.

2.6. Study Design The scientific integrity of the study and the credibility of the data from the study depend substantially on the study design. A description of the study design should include:

• A description of the type/design of study to be conducted (e.g., placebo-controlled, double mask, parallel design, open-label, dose-escalation, dose-ranging) • A description of the study population (e.g., healthy/sick, in-patient/out-patient) • A discussion of the rationale for design features • Phase of trial • Single or multicenter • The number of study groups/arms • Prospective or Retrospective or Cross-sectional study • Description of study groups/arms including sample size (including a table, if appropriate) • Approximate time to complete study enrollment • The expected duration of participant participation • Identification of the test agent and specifics of administration of other agents (e.g., placebo) • A description of the sequence and duration of all trial periods, including follow-up (specify individual participants vs. entire trial) • Changes in scheduling, such as dose escalation • Any stratifications

General Guidelines for Clinical Evaluation of Ayurvedic Interventions • Methods for collecting data for assessment of study objectives

• Other protocol-specific details, such as centralization of evaluations (e.g., central laboratory or central reading center for clinical scans)

• Interim analysis plans

2.6.1. Phases of clinical trial for Ayurvedic drug / Patent or Proprietary Medicines A systematic study of Ayurvedic drug / Patent or Proprietary Medicines on human participants - (Whether participants or non-participant volunteers) - in order to discover or verify the clinical, pharmacological (including pharmacodynamics / pharmacokinetics), and / or adverse effects, with the object of determining their safety and / or efficacy.

2.6.1.1. Human Pharmacology (Phase I) i. The objective of studies in this Phase is the estimation of safety and tolerability with the initial administration of an Ayurvedic Drugs / Patent or Proprietary Medicines into human(s). Studies in this Phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteers or certain types of participants. Ayurvedic drug / Patent or Proprietary Medicines with probable toxicity e.g. Ayurvedic drug / Patent or Proprietary Medicines with Schedule E-I ingredients are to be studied in participants. Phase I trials should preferably be carried out with access to the necessary facilities to closely observe and monitor the Participants. ii. Studies conducted in Phase I, usually intended to involve one or both of the following objectives:- a. Maximum tolerated dose: To determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies include both single and multiple dose administration. b. Early measurement of Drug activity: Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective. Such studies are generally performed in later Phases but may be appropriate when drug activity is readily measurable with a short duration of drug exposure in participants at this early stage. 2.6.1.2. Therapeutic exploratory trials (Phase II) i. The primary objective of Phase II trials is to evaluate the effectiveness of an Ayurvedic drug / Patent or Proprietary Medicines for a particular indication or indications in

participants with the condition under study and to determine the common short term side-effects and risks associated with the drug. Studies in Phase II should be conducted in a group of participants who are selected by relatively narrow criteria leading to a relatively homogeneous population. These studies should be closely monitored. An important goal for this Phase is to determine the dose(s) and regimen for Phase III trials. Doses used in Phase II are usually (but not always) less than the highest doses used in Phase I. These studies should be intended to provide an adequate basis for marketing approval for Ayurvedic drug / Patent or Proprietary Medicines. ii. Additional objectives of Phase II studies can include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further studies in Phase II or III. iii. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.

2.6.I.3. Therapeutic confirmatory trials (Phase III) i. Phase III studies have primary objective of demonstration or confirmation of therapeutic benefits(s). Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. Studies in Phase III may also further explore the dose-response relationships (relationships among dose, and clinical response), use of the drug in wider populations in different stages of disease, or the safety and efficacy of the drug in combination with other drug(s). ii. For Ayurvedic drug / Patent or Proprietary Medicines intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in Phase III, although they may be initiated in Phase II. These studies carried out in Phase III complete the information needed to support adequate instructions for use of the drug (prescribing information). iii. For Ayuvedic drug / Patent or Proprietary Medicines approved outside India, Phase III studies needs to be carried out primarily to generate evidence of efficacy and safety of the Ayurvedic drug / Patent or Proprietary Medicines in Indian participants when used as recommended in the prescribing information. Prior to conduct of Phase III studies in Indian participants. iv. If the application is for the conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and participants as well as the justification

General Guidelines for Clinical Evaluation of Ayurvedic Interventions for undertaking such trials in India should be provided to the Licensing Authority along with the application.

2.6.I.4. Post Marketing Trials (Phase IV) Post Marketing trials are studies (other than routine surveillance) performed after drug approval and related to the approved indication(s). These trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. These trials may not be considered necessary at the time of new drug approval of Ayurvedic drug / Patent or Proprietary Medicines but may be required by the Licensing Authority for optimizing the drug’s use. They may be of any type but should have valid scientific objectives. Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc.

NOTE: • For classical Ayurvedic drugs with same textual indications, directly phase III/IV trial may be conducted. • For classical Ayurvedic drug with new indications/Patent or Proprietary Medicines, directly phase II trial may be conducted. • Patent or Proprietary Medicines with Schedule E-I ingredients, Phase I trials may be conducted as appropriate.

2.6.2. Types of the clinical study A clinical study involves research using human volunteers (also called participants) that is intended to add to medical knowledge. There are mainly two types of clinical studies: experimental studies and observational studies. 'Brief descriptions of these studies are as under:

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Figure 5: Types of clinical studies

2.6.2.I. Observational Study

An observationalstudy is one which tries to explore the cause-and-effect relationships. Like experimental study the Investigators is not able to control the participants by allocating in groups or assigning any particular treatment. The Investigators only observe the participants involved and their responses by asking questions, or taking some measurements, or looking at clinical records. A sample survey is an example of an observational study. Followings are observational studies:

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 11 Case series studies: Case-series is a descriptive study design wherein a series of cases of any particular disease that one might observe in one's clinical practice, hospital and so on is presented. There is no control group in this type of study. In terms of evidence, this is a weak study design but it can help provide leads in designing research studies.

Case reports: Documentation of reports on a single participant constitutes case reports. They do not use control groups and hence do not have high statistical validity or cannot provide conclusion about the causality but can provide leads to formulation of a hypothesis for potentially high impact research studies.

Case control studies: When a correlation is drawn between factors or exposures as causal in participants who have a specific health condition. These studies are retrospective when the history and reports of the participant is analyzed and a correlation is drawn if they might have been causal. This is compared with the history and reports of participants who do not have the health condition. This level of evidence in such studies is low when compared to randomized controlled trials or cohort studies because just a statistical association do not necessarily conclude cause and effect relationship. For example- tobacco and cancer.

Cohort studies: A ‘cohort’ meaning is a population who are exposed to similar environmental conditions. This is a kind of observational study where one group of a cohort with exposure to a particular causative agent or a treatment is compared with a similar group who are not exposed. They are followed up prospectively. The level of evidence here is lower when compared to randomized controlled trials. For example, tobacco use among working and none working adolescents.

Cross sectional studies: A cross sectional study is an observational study that aims at determining the exposure and prevalence of disease at the same point in time in a given population for e.g., prevalence of post traumatic stress disorders in people after Tsunami. It can also be used in determining the sensitivity and specificity of new diagnostic tests.

2.6.2.2. Experimental Study

In a clinical trial, participants receive specific interventions according to the research plan or protocol created by the Investigators. These interventions may be medical products, such as drugs or devices; procedures; or changes to participants' behavior, such as diet. Clinical trials may compare a new medical approach to a standard one that is already available, to a placebo that contains no active ingredients, or to no intervention. Some clinical trials compare

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interventions that are already available to each other. When a new product or approach is being studied, it is not usually known whether it will be helpful, harmful, or no different than available alternatives (including no intervention). The investigators try to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants. The scientific integrity o f the trial and the credibility o f the data from the trial depend substantially on the trial design.

Single arm trials: Single arm trial is the simplest trial design. A sample of participants with a particular disease is administered an intervention and the effect is measured after a decided period of time to observe the response. This design is adopted where placebo effect is minimal or there is no scope for incorporating or it is unethical to include a placebo arm. The level of evidence is low in this design usually. However, it is apt for validation o f Panchakarma procedures, application o f leech, Agnikarma, Ksharasutra, etc.

Cross over trials: In a cross over design, the objective is to compare the effect of therapies. The trial participant is randomly allocated to one treatment protocol for a period of time and then later after a wash out period, the same participant is randomly allocated to another treatment protocol and the effects of treatments are compared.

Factorial Trials: Factorial designs are considered when the objective of the study is to compare effects of a minimum of two treatment protocols either alone or in combination. For example, if there are two interventions A and B then group-1 is given intervention A, group- 2 is given B, group- 3 is administered both A and B and group- 4 is given neither. Factorial designs are considered when the effects o f more than two interventions are to be evaluated.

Non inferiority trials (Active Controlled trials): This type of trial design consists of testing the effect of a particular treatment in comparison with an available standard treatment. Non inferiority trials are designed to effectively evaluate the effect of a particular intervention where incorporation of a placebo group is unethical.

Parallel design: Placebo controlled trials: A placebo is an agent that produces an effect on the disease through a psychological mechanism i.e., through a non specific effect which does not comply with a definable, physiological mechanism. Therefore, placebo effect needs to be nullified to prove that drug /therapy /formulation intended to produce an effect on the disease occurs genuinely through a definable bio - physiological mechanism. Placebo controlled design with randomization and blinding produces highest evidence. They require large sample sizes.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 13 Three arms trial: Placebo & active control: This design involves inclusion of a placebo as well as an active control group and provides good internal evidence of sensitivity.

Add on Study: An add on study is a placebo-controlled trial wherein a new agent is concomitantly administered in participants in addition to receiving a standard treatment. These kind of studies are useful when the existing treatment is not fully effective and there is evidence that another treatment in addition can bring about better outcomes and if there are no adverse drug reactions or interactions.

Replacement study: In this design a new drug or placebo is randomly added to the conventional treatment and the conventional treatment is then slowly withdrawn usually by tapering. This design can effectively evaluate the ability of the participant to maintain the baseline status after withdrawal of the conventional treatment.

Early escape rescue treatment: If in a trial, administration of a treatment protocol is either ineffective or if it results in worsening of the disease and who otherwise would require a rescue treatment like in seizures or angina then the trial treatment is withdrawn. Here the need to change the treatment becomes the study end point. This design evaluates short term effectiveness of a treatment protocol.

Limited placebo period: In situations where it is not possible to continue the participants for long duration of placebo administration the placebo group is maintained for a short duration and then the trial would go on with an active control group without the placebo group. This design evaluates short term effectiveness of a treatment protocol.

Additional doses design: This design involves randomizing participants into parallel groups of different fixed doses of a certain treatment protocol. This design evaluates dose based response.

Randomized withdrawal: In this design participants getting a test treatment for a particular period of time are randomly assigned to continued test treatment and placebo. Difference between those receiving continued treatment and those on placebo reveals the effect of active treatment and evaluates the status of remission or aggravation of a particular disease and long term efficacy.

No-treatment concurrent control: No treatment concurrent control design involves randomization of participants into test treatment and no treatment. This design can be used when it is not possible to use double blinding.

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External control (including historical control): This is a comparative trial where participants receiving an active treatment is compared with a control from another study at another setting at the same point of time (External control) or if it is taken from a study conducted at an earlier point of time (historical control) it is known as external control. Designs Amenable to test Ayurvedic Therapies

Black-box design Generally Ayurvedic treatments are not just isolated administration of a therapeutic molecule or a single drug but, are a combination of drugs/procedures that constitute a therapy for a particular health condition for a particular individual. Therefore, a traditional treatment that may consist of a set of therapeutic procedures should be considered as one single module which is studied in comparison with either placebo or a standard treatment. This allows the Ayurvedic treatments to be determined within its theoretical framework and not compromising with the fundamental principles of traditional medicine.

Reverse Pharmacology Design In the realm of traditional medicines, many herb based medicinal formulations have known to have healing effects on many health conditions but such results have not been pursued rigorously through research studies to know the effect of such medications in various complex biological systems. Therefore the concept of reverse pharmacology (RP) helps in addressing the issue where the effect of the Ayurvedic formulation on a health condition is known but the mechanism of action is not known. In this approach the drug candidate travels a reverse path from ‘clinics to laboratory’ rather than classical ‘laboratory to clinics. This concept has three phases as follows RP-Phase I: This involves an experiential phase where comprehensive documentation of clinical observations of the effect of standardized Ayurvedic drug on the biological systems is done.

RP-Phase II: The purpose of this phase is to evaluate the target activity of the Ayurvedic formulation/drug/Therapy under in-vitro and in-vivo models and exploratory studies for tolerability, drug-interactions and dose-range.

RP-Phase III: The purpose of this phase is to carry out basic and clinical studies at several levels of biological organization and to identify and correlates of drug safety and efficacy. Studies in this phase should be able to decipher mechanisms of action at multiple biological systems and to optimize safety, efficacy and acceptability of the leads in natural products based on relevant science.

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Ethnographic design for folk claims Ethnographic design is one that is used in validation of traditional medical practices. There might be claim of a healing practice from a traditional socio cultural setting in a particular locality. This claim might not have scientific evidence or other documentation. This can become basis from which hypotheses may be generated, and can lead to further research. Designing a placebo in most of the Ayurvedic interventions is not possible as principles of Ayurveda follow the system biology approach where the response to a therapy is evaluated in terms of the body as a whole and not confined individual system. Most of the drugs are also poly formulations consisting of ingredients from plant, mineral and animal origins and not an active molecule as in case of the modem system of medicine. It is very difficult to have the trial drug and placebo are prepared in a way that they are similar in colour, taste, size, weight, same smell and same consistency. Therapy in Ayurvedic system of medicine also involves procedural interventions like Panchakarma in Ayurveda and so on for which designing placebo becomes impossible. In such cases, appropriate control groups can be incorporated like active controls or no interventions etc. Different controls can be used in clinical trials to answer different questions. The use of a placebo, when possible, is desirable, because it generates evidence of better quality. Placebo- controlled trials are intended to establish whether treatment is valuable over and above what might be achieved by a control treatment, and not whether treatment is valuable at all. Thus, it allows Investigators to distinguish specific from non-specific effects of treatment in order to determine whether the additional cost, risk and effort of a specific treatment are worthwhile. It is also important for understanding the mechanism of a treatment. This is true for the evaluation of all drugs. It is not only of academic interest, but is also practical value, especially for developing new treatments from traditional ones. However, in some cases, placebo controlled trials may not be possible.

2.6.2.3. Data Based Studies

Systematic reviews: These are studies based on already published studies. A certain review criteria is decided and with a sound methodology, the results of the published studies are scrutinized and summarized for e.g., Effect of herbal medicines with significant effect on Hamilton depression rating scale in participants suffering from depression.

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Meta Analysis: These studies are also based on already published studies. The study compiles and examines the results of number of valid studies on a particular topic and consolidated results are presented for example Meta-analysis of RCTs on the anxiolytic effect of Ashwagandha.

Data based studies on Ayurvedic drugs can provide much needed evidence to recommend use of Ayurvedic interventions among scientific community.

Conventionally, the level of evidence is ranked in order of risk of bias and from top to bottom ranked as Meta-analyses, Systematic reviews, Interventional studies, Observational studies and experts' opinions. (See Annexure III- Level of evidence)

However, due to classical textual evidence, long history of use and vast clinical experience, this hierarchical ranking of level of evidence may not be completely apt for Ayurveda and its approaches.

2.7. Randomization Randomization is used to develop comparable groups to assess therapeutic interventions. It is essential to control various known, and even unknown, biases. Nevertheless, there are many situations where randomization can be impossible or unethical. The best way to solve this problem is probably by the proper selection of control treatments.

2.7.1. Randomization method and procedure (wherever applicable)

Simple random samples: This is a procedure where each individual of a population has equal probability of being selected. A simple random sample is representative of a population and gives external validity. The results obtained have good generalize ability of results. Random number generators are available online. It can also be generated using excel sheet.

Random allocation: Random allocation is a procedure of randomly allocating an identified sample to different groups. Each participant has the same probability of being assigned to a particular group.

Block randomization: This randomization procedure helps in achieving same sample size in two or more groups. Block randomization is done by generating random permuted blocks (blocking). For e.g., in a block size of six consecutively enrolled participants three can be allocated to one treatment group and three to another. The ratio of allocation can also change. This method helps in interim analysis.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 17 Stratified randomization To avoid imbalances among baseline characteristics, pre-randomization stratification is done based on requirement like Age, Gender, prognostic factors etc.

2.7.2. Methods of blinding

Blinding is a process of ensuring that the people involved in a research study (participants or investigators) do not know about what treatment they are receiving. This procedure is incorporated to minimize the biases that arise due to differences in treatment, management, investigator who is carrying out the study, rather who assesses the participants or one who interprets the results. These biases arise because participants who know about the active treatment might report more favorable outcomes. The Raters or Investigators who know about the treatment may over enthusiastically rate the response to a treatment or they might undermine the response to placebo or no treatment. Knowledge of treatment might influence the people to use favorable statistical tests. Open: The participants, investigators, and data analyst know about what treatment they are receiving. Single blind: Here either the participant or investigator does not know about the treatment. Double blind: Here neither the participant nor the investigator knows about the treatment. Triple blind: This is a blinding procedure in which the participant, the investigator and the data analyst does not know about the treatment.

2.7.3. Randomization Codes and Procedures for Breaking the Code

Breaking the codes/Un-blinding in case of emergency Randomization codes are computer generated. Requirement for unblinding arises out of an emergency. The Investigator gets the primary information about the emergency and therefore he should have a developed mechanism for breaking the codes. The investigator should access to sealed envelopes 24 hours a day. He can also delegate a suitable person to carry out the code break. The sponsor should be notified about the code break within 24 hours. In a non emergency situation the code- break cannot be done without the approval of the sponsor. Breaking the codes/Un-blinding at the end of the trial Breaking the codes/un-blinding is done by a formal request to the Sponsor and head of the Institute but should not be done until the following events have been completed • Completion of last follow up of the participant • All data has been entered and validated and there is no scope for further changes

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• It is better that the statistician is also blinded until the analysis is complete. information on establishment o f study code, where it will be kept and when, how, and by whom it can be broken in the event o f an emergency.

Allocation concealment Allocation concealment is a procedure that ensures that either participants or investigators does not know what is being received by the participant. Ideally, the procedure is done as follows: The trial drug and placebo are prepared in a way that they are similar in colour, taste, size, weight and smell. In double blind study a random sequence of codes is generated centrally and assigned to the prospective participants. Sequentially numbered sealed opaque coded envelopes with aluminium foils to prevent revealing against bright light are assigned to each trial participant with details of the treatment inside. After obtaining the consent, the random code is assigned to the participant. The envelopes are generally stored in the pharmacy and the pharmacist gives the containing drug or placebo to the participant. In single blind studies where the investigator knows about what the participant is going to receive, the centrally generated random sequence of numbers is assigned to the prospective participants in terms of who is going to receive drug or placebo. The sequentially numbered sealed envelopes are coded for drug or placebo. The codes should not be in such a way that if the un-blinding is done for one participant in case of emergency then, it should not reveal the codes for all the participants. For example, if ‘0’ is used to code placebo and ‘1’ to drug, then if an emergency situation necessitates, un-blinding the information about all the participants is automatically revealed. The codes could be generated and kept by the sponsor / central funding agency and will be broken by them in case of emergency.

Documentation of decoding during the study Following information needs to be documented before code break- • The identity of the person requesting code break • Reason for requesting the code break • Bottle or box number of the trial medication • Participant number • Name of the person authorizing the code break procedure *This information should be documented and preserved along with the case record form

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 19 Blind assessment Blind assessment is a critical component of conventional evaluation of therapeutic interventions. However, in the evaluation of efficacy of procedure-based therapies (such as Panchakarma therapy, Ksharasutra, Agnikarma, Jalauka therapy, etc) and Multi drug regime it may be difficult, impractical or impossible for the Investigator to be kept ignorant of what treatment the participants are receiving.

Treatment blinding in the evaluation of Ayurvedic medicines should adopt the approach of conventional medicines, e.g. using active and control formulations with similar appearance, taste and weight. However, if the Ayurvedic medicine cannot be administered in a predetermined standardized formulation, it will be impossible to keep the treatment blinded.

2.8. Study period 2.8.1. Total duration of the study Mention the total duration of the study from preparatory phase to analysis of the data.

2.8.2. Timelines with deliverables A timeline is a way of displaying a list of events in chronological order to be happened in the project. Project timeline outline the deliverables (important milestones and task) of a project in chronological sequence. This helps all project resources and stakeholders see what deliverables need to be accomplished next and by what date. Having a visual project timeline that clearly communicates the important milestones and tasks is an essential tool for successful planning or project management. An example is given below-

Deliverables Time Lines Pre-trial preparations: Procurement of drugs and equipment, 1-3 months engagement of staff, preparation of CRFs, Institution ethical clearance, arrangement for laboratory investigations, publicity, registration in the CTRI wherever applicable Recruitment and data collection 4-18 months Data compilation and analysis 19-24 months

Duration of the Treatment:Duration of the participant participation and a description of the sequence of all study periods including follow-up, if any should be recorded.

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2.9. Sample Size considerations The number of participants in a study needs to be adequate, in order to be able to determine any clinically important differences (outcome measures) between the study groups. For this purpose provide all information needed to validate the calculations for sample size, and also to judge the feasibility of enrolling and following the necessary numbers of participants. In particular, specify all of the following: • Outcome measure used for calculations (almost always the primary variable) • Test statistic • Null and alternate hypotheses • Type I error rate • Type II error rate • Assumed event rate for dichotomous outcome (or mean or variance of continuous outcome) for each study arm, justified and referenced by historical data as much as possible • Assumed dropout rates, withdrawal, cross-over to other study arms, missing data, etc., also justified • Approach to handling withdrawals and protocol violations, i.e., whether participants will be included in the “intent-to-treat” population • Statistical method used to calculate the sample size, with a reference for it and for any software utilized

2.10. Participant enrollment and withdrawal 2.10.1. Participant Inclusion Criteria Provide a statement that participant must meet all the inclusion criteria in order to be eligible to participate in the study and then list each criterion. Example: • Willing to participate and comply with all study procedures for prescribed trial period. • Willing for giving the written consent • Age and gender • Clinical Signs and symptoms fit for the diagnostic criteria of the specific disease condition of the trial • Laboratory parameters within a specific range

2.10.2. Participant Exclusion Criteria Provide a statement that any participant meeting any of the exclusion criteria at baseline will be excluded from study participation and then list each criterion.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 21 Example: • Medical condition, laboratory finding, or physical exam finding (e.g., vital signs outside of specific range) that precludes participation

• Use of disallowed concomitant medications (specify)

• Pregnancy or lactation

• Known allergic reactions to components of the study product(s)

• Treatment with another investigational drug or other intervention (within a specified time frame)

• History of drug/alcohol abuse

• Characteristics of household or close contacts (e.g., household contacts who are immune- compromised, residence in same household as a participant already participating in study, if blinding or compliance could potentially be compromised)

• Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude the participant’s full compliance with or completion of the study.

2.10.3. Withdrawal criteria Reasons for Withdrawal and handling of withdrawals Provide a list of reasons participants may be discontinued from the study. It may be appropriate to provide distinct discontinuation criteria for participants. Also note that participants may withdraw voluntarily from participation in the study at any time. Participants may also withdraw voluntarily from receiving the study intervention for any reason. Example: • Any clinical adverse events (AE), laboratory abnormalities, inter current illness, or other medical condition or situation occurs such that continued participation in the study would not be in the best interest of the participant. • The participant meets any exclusion criteria (either newly developed or not previously recognized). Handling of Withdrawals Describe the efforts to follow participants who withdraw from the study. It is vital to collect safety data of any participant discontinued because of an AE or SAE. In any case, every effort must be made to undertake protocol-specified safety follow-up procedures and be given appropriate care under medical supervision until the symptoms of any AE resolve or the

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participant’s condition becomes stable. If voluntary withdrawal occurs, the participant should be convinced by the Investigator to complete an end-of-study evaluation.

2.11. Study Procedures 2.11.1. Screening Screening is the procedure to evaluate the eligibility of participant to include /exclude in the study. The investigator / Institution shall also maintain a Participants’ screening register to document identification of Participants who are screened for the research study.

2.11.2. Enrollment/Baseline visit A Participant’s enrolment register apart from the screening register shall also be maintained to document chronological enrolment of Participants in a particular Study. The baseline visit will be the first day for initiation of the therapy/treatment of enrolled participants/participants.

2.11.3. Follow-up Visit The follow up visits are the subsequent visits attended by the participant in prescribed time period as per the study protocol.

2.11.4. Final Study Visit The final visit is the day of completion of the treatment/study period (follow up period without therapy/treatment, if any) as per the study protocol.

2.11.5. Re-scheduled V isit-if any Re-scheduled visit is the case where the appointment on the scheduled day is not feasible due to certain reasons e.g. either the participant or investigator is not available, etc.

2.11.6. Early Termination Visit-if any Early termination visit is the case where the participant develops either any serious ADR/ADE or non-compliance of the treatment regimen / termination of the study, etc. The same needs to be informed to the Sponsor and the Ethics Committee within two working days.

2.11.7. Laboratory Evaluations The investigations should be done preferably from NABL accredited laboratories. In case of multi-centre studies, the sponsors will take necessary step for selection of a central laboratory taking into consideration that the branches of such laboratories exist at the vicinity of all participating centers and selected laboratory will not further outsource any of the investigations.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 23 Methodology, chemicals/kits, equipments and/ or the reference value of the investigations should be uniform at all centers.

2.11.8. Efficacy evaluation(Assessment criteria) Efficacy of trial drug/therapy /procedure is to be assessed on following parameters. 1. Sign and symptoms of concerned disease 2. Laboratory parameters 3. Samyak Lakshana of therapy/procedures

2.11.9. Assessment of safety • Specifications of safety parameters (both laboratory parameters and signs & symptoms) • Methods/ Procedures and periodicity for assessment and analysis of safety parameters • Designing a specific format for reporting and recording adverse drug events/effect or inter-current illnesses.

2.11.9.1. Adverse Reactions (ADR) / Adverse Events (AE) An unexpected ADR requires expedited review by the Institutional Ethics Committee (IEC). Unexpected AE/ADRs and all SAE (serious adverse event) should be reported to the sponsor by the investigator within 24 hours and to the IEC that accorded approval to the study protocol within seven days. At the end of the trial, all adverse events whether related to trial or not are to be listed, evaluated and discussed in detail in the final report. The medical management of the adverse event is the responsibility of the investigator, and the protocol for adverse event management with allocation of responsibilities must be pre-defined in the protocol and submitted to the Institutional Ethics Committee. The Sponsor should provide ADR/AE reporting forms to the Investigator(s) / Institution(s). The Sponsor should expedite the reporting to all concerned (including the Ethics Committee and the regulatory authorities) of all serious and/or unexpected adverse drug reactions.

2.11.9.2. Serious Adverse Events Any unexpected SAE as defined in the Indian GCP (Good Clinical Practice) Guidelines occurring during a clinical trial should be communicated promptly within 14 calendar days by the Sponsor to the Licensing Authority and to the Investigator(s) of other trial sites participating in the study. The reporting of the SAE to the regulatory authority immediately is to enable it to stop the clinical trials of unapproved drugs or withdraw from market approved drugs based on report of Phase IV studies. All other serious unexpected reactions (ADRs) that are not fatal or

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life threatening must be filed as soon as possible but not later than 14 calendar days. In the event of death the EC should also be informed within 24 hours. * Collection o f laboratory data should be limited to those laboratory parameters that are relevant to safety, study outcome measures, and/or clinical outcome. The toxicity tables will define what values or findings are considered abnormal. Reporting will be dependent on the abnormality, the study intervention, and the study population and should be stated specifically. Consider the context of the trial and adjust reporting procedures appropriately for the study population and agent being studied.

2.12. Rescue Medication A medication intended to relieve symptoms of the investigated disease immediately. To alleviate any emergency, the use of rescue medication is permitted as per the wisdom/discretion of the Investigator. This is in contrast to preventive medications, which are taken over a long period of time to prevent or manage symptoms (for example: Use of NSAIDs for relief of severe pain in case of trial participants of Vatarakta (Gouty Arthritis) is the rescue medication in contrast to uricosuric agent such as Allopurinol, etc.).

*The details o f the given rescue medication should be recorded with the details o f the name, dosage form, dose, duration, etc. in the Case Report Form.

2.13. Concomitant Medication A concomitant medication (con-med) is a drug or biological product, other than a study drug, taken by a participant during a clinical trial for any other medical condition (for example: Simultaneous use of anti-hypertensive drug in a known case of hypertension enrolled in the trial of any other disease conditions). *The details of concomitant medications prescribed to the participants should be properly recoded with the details o f the name, dosage form, dose, duration, etc. in the Case Report Form. The participants will be instructed to avoid the use o f any other drugs on their own for any ailment and will be clearly instructed to consult the treating Investigator for any symptom or complaint, or if they feel anything unusual.

2.14. Statistical Analysis The type(s) of Statistical Analysis to be used must be clearly identified and should form basis of the statistical model for the Study. Any subsequent deviation(s) should be described and justified in the Final Report. The need and extent of an interim analysis must be specified in the Protocol. The results of the statistical analyses should be presented in a manner that is likely to facilitate

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 25 the interpretation of their clinical importance, e.g. by estimates of the magnitude of the treatment effect / difference and confidence intervals rather than sole reliance on significance testing. Missing, unused and spurious data should be accounted for during the statistical analyses. All such omissions must be documented to enable review.

2.15. Criteria for the Discontinuation of the Study (Partial Or Whole)/ Termination of study Study Discontinuation is the case where the participant develops either any serious ADR/ADE or non-compliance of the treatment regimen / termination of the study, etc. The same needs to be informed to the Sponsor and the Ethics Committee within two working days. Further, the discontinuation of a trial should be ordered if the IEC finds that the goals of the trial have already been achieved midway or unequivocal results are obtained.

The study may be prematurely terminated if, in the opinion of thelnvestigator or the Sponsor or the Data Safety Monitoring Board (DSMB) there is sufficient reasonable cause. Written notification, documenting the reason for study termination, will be provided by the terminating party.

Circumstances that may warrant termination include, but are not limited to: • Determination of unexpected, significant, or unacceptable risk to participants. • Insufficient adherence to protocol requirements. • Data that is not sufficiently complete and/or evaluable. • Plans to modify, suspend or discontinue the development of the study drug.

If the study is prematurely terminated or suspended, Sponsor will promptly inform the investigators/institutions, and the regulatory authority (ies) about the termination or suspension and the reason(s) for the termination or suspension. The Independent Review Board (IRB)/ Independent Ethics Committee (IEC) will also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the Investigator /Institution, as specified by the applicable regulatory requirement(s).”

* All studies that are still analyzing data or samples (even if accrual has stopped) are submitted to the IRB/IEC for continuing review as per IRB policies. The IRB does not review the consent form, although under the IRB continuing review rules the consent form must be resubmitted with continuing review.

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2.16. Monitoring, Auditing and Data & Safety Monitoring Board (DSMB) It is mandatory that all research proposals on involving human participants should be cleared by an appropriately constituted Institutional Ethics Committee (IEC), also referred to as Institutional Review Board (IRB) or Ethics Review Board (ERB). The Ethics Committees are entrusted not only with the initial review of the proposed research protocols prior to initiation of the study but also have a continuing responsibility of regular monitoring of the approved programs to foresee the compliance of the ethics during the period of the study.

Local Monitoring The Head of the Institute/Center would ensure periodic review and monitoring of the projects at Institute/Center level and the same needs to be reflected in the progress report of the institute that is being communicated to the Sponsor.

Central Monitoring In case of multicentre studies a Central Monitoring Committee should be constituted to monitor the activities as and when required.

*Template for Monitoring is annexed at Annexure -IV.

Auditing Sponsor should perform an audit as a part of QA system. This audit should be conducted with the purpose of being independent and separate from routine monitoring or quality control functions. Audit should evaluate the study conduct and compliance with the protocol, SoPs, GCPs and applicable regulatory requirements. For the purpose of carryingout the audit - the sponsor may appoint individuals qualified by training and experienceto conduct audits. The Auditors should be independent of the parties involved in thestudy and their qualifications should be documented. The Sponsor should ensure that the auditing is conducted in accordance with the Sponsor’sSOPs on what to audit, how to audit, the frequency of audit and the form & content of audit reports. Auditors should document their observations which should be archived by the Sponsors and made available to the Regulatory Authorities when called for.

Sponsor should initiate prompt action in case it is discovered that any party involved hasnot entirely complied with the GCP, SOPs, Protocol and / or any applicable regulatory requirements. If monitoring / auditing identifies serious and / or persistent noncompliance- the Sponsor should terminate the defaulting party’s participation in the study and promptly notify to the regulatory authority.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 27 Data & Safety Monitoring Board The Data and Safety Monitoring Board (DSMB) is a board, charged with monitoring the accumulating datafrom a pharmaco-therapeutic clinical trial to detect and report early evidence of pre-specified orunanticipated benefit or harm to trial participants that may be attributable to one of the treatmentsunder evaluation. The DSMB will conduct an independent, objective review of all accumulated datafrom both blinded and unblinded clinical trials in such a manner as to maximize benefit to the trial participants and to the research effort. A Data and Safety Monitoring Board (DSMB) may be established to carefully monitor the data and side effects during the period of the study and put in a place where by prompt reporting of adverse event occur. The data should be reviewed at regular intervals. The Research team should report immediately to the Investigators) and Data and Safety Monitoring Board regarding any life threatening condition, whether they are pursued to be study related or not. (Please see the DSMB guidelines at Annexure-V)

3. Ethics and Safety Consideration 3.1. Ethical Principles All researches involving human participants should be conducted in accordance with the ethical principles and should respect four basic principles namely justice, respect for persons (autonomy), beneficence (to maximize benefits and to minimize harms and wrongs) and non malaficence (to do no harm) for dignity, safety, right and wellbeing of the study participants as defined in revised “National Ethical Guidelines for Biomedical and Health Research Involving Human Participants ” issued by the Indian Council of Medical Research and any other laws and regulations of the country. The following principles are to be followed for conducting a research: Principles of essentiality: The principle says that after thorough consideration of all alternatives in the proposed area of research, the participation of human being for a research is considered to be essential. This should be duly vetted by an Ethics committee independent of the proposed research. Principles of voluntariness: To agree or not to agree to participate in research, or to withdraw from research at any time, the decision of the participant is supreme as per the principle. The informed consent process ensures that participants’ rights are safeguarded. Principles of non-exploitation: As per this principle, the selection of the participants in aresearch and thebenefits and burdens of the research should be distributed fairly without any

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discrimination irrespective of their social and economic condition or status, or literacy or educational levels. Sufficient safeguards to protect vulnerable groups should be ensured. Principle of social responsibility: The research should be planned and conducted meticulously to avoid the creation or deepening of social and historic divisions or in any way disturb social harmony in community relationships. Principles of privacy and confidentiality: The principle says the privacy of the participant, her/his identity and records are kept confidential and access is limited to only those authorized. However, under certain circumstances (suicidal ideation, homicidal tendency, HIV positive status, when required by court of law etc.) privacy of the information can be breached in consultation with the IEC for valid scientific or legal reasons as the right to life of an individual supersedes the right to privacy of the research participant. Principles of risk minimization: As per this principledue care is taken by all stakeholders (including but not limited to researchers, IECs, sponsors, regulators) at all stages of the research to ensure that the risks are minimized and appropriate care and compensation is given if any harm occurs. Principles of professional competence: The principle says that the person/Researcher involved in planning, execution, evaluation and monitoring of a research should be competent and having the appropriate and relevant qualification, experience and/or training. Principles of accountability and transparency: As per this principle, the research plan and outcomes emanating from the research should be brought into the public domain through registries, reports and scientific and other publications while safeguarding the right to privacy of the participants. Stakeholders involved in research should disclose any existing conflict of interest and manage it appropriately. The research should be conducted in a fair/,honest, impartial and transparent manner to guarantee accountability. Related records, data and notes should be retained for the required period for possible external scrutiny/ audit. Principles of the maximization of benefits: Due care should be taken to design and conduct the research in such a way that the research participants and/or the society directly or indirectly will get maximum benefits from the research. Principles of institutional arrangements: The institutions responsible for conducting the research should have policies for appropriate research governance, and take the responsibility to facilitate research by providing required infrastructure, manpower, funds and training opportunities.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 29 Principles of totality of responsibility: All stakeholders involved in research are responsible for their actions. The professional, social and moral responsibilities compliant with ethical guidelines and related regulations are binding on all stakeholders directly or indirectly. Principle of environmental protection: There searchers in compliance with existing guidelines and regulations are accountable for ensuring protection of the environment and resources at all stages of the research.

3.2. Ethics Committee The Sponsor and / or Investigator should seek the opinion of an Institutional Ethics Committee regarding suitability of the Protocol, methods and documents to be used in recruitment of Participants and obtaining their Informed Consent including adequacy of the information being provided to the Participants. The Ethics Committees are entrusted not only with the initial view of the proposed research protocols prior to initiation of the projects but also have a continuing responsibility of regular monitoring for the compliance of the Ethics of the approved programs till the same are completed. Such an ongoing review is in accordance with the “Ethical guidelines for Biomedical Research on Human participants” 2006, as amended from time to time by Indian Council of Medical Research, New Delhi.

3.2.1. Basic Responsibilities The basic responsibility of an IEC is to ensure a competent review of all ethical aspects of the project proposals received and execute the same free from any bias and influence that could affect their objectivity. The IECs should specify in writing the authority under which the committee is established, membership requirements, the terms of reference, the conditions of appointment, the offices and the quorum requirements.

3.2.2. Composition of IEC a. IEC should be multidisciplinary and multi-sectorial in composition. Independence and competence are the two hallmarks of an IEC. b. The number of persons in an Ethics Committee to be kept fairly small (5-7 members). It is generally accepted that a minimum of five persons is required to compose a quorum. There is no specific recommendation for a widely acceptable maximum number of persons but it should be kept in mind that too large a committee will make it difficult in reaching consensus opinion. 12 to 15 is the maximum recommended number c. The Chairperson of the committee should preferably be from outside the Institution and not head of the same Institution to maintain the independence of the committee. The Member

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Secretary who generally belongs to the same Institution should conduct the functioning of the Committee. Other members should be a combination of medical/non-medical, scientific and non-scientific persons including lay person to reflect the differed viewpoints. The composition may be as follows:- 1. Chairperson- A technical person with research background 2. Member secretary 3. Clinicians -1-2 Ayurvedic practitioners/ clinicians from different Institutes 4. Basic medical scientists- 1-2 basic medical scientists (one pharmacologist and one preferably from Dravyaguna / Rasa shastra / Bhaishajya Kalpana). 5. Legal Expert- One Legal expert or retired Judge 6. One Social Scientist / philosopher / ethicist / theologian / representative of Non- Governmental Voluntary Agency 7. One lay person from the community The Ethics Committee at any Institution can have as its members, individuals from other Institutions or Communities if required. There should be adequate representation of age, gender, community; etc. in the Committee to safeguard the interests and welfare of all sections of the community/Society. Members should be aware of local, social and cultural norms, as this is the most important social control mechanism. If required concerned subject experts could be invited to offer their views. *In case where the IEC approval will be obtained is non AYUSH organization, two experts from Ayurveda should be kept as IEC members.

3.2.3. Terms of Reference for IECs The IEC members should be made aware of their role and responsibilities as committee members. Any change in the regulatory requirements should be brought to their attention and they should be kept abreast of all national and international developments in this regard. The Terms of References should also include a statement on Terms of Appointment with reference to the duration of the term of membership, the policy for removal, replacement and resignation procedure etc. Each committee should have its own operating procedures available with each member. • The TOR for the IEC and its members should be clearly specified by the institution in the IEC SoPs (Please refer Annex VI for the List o f SoPs/ • Every IEC should have written SoPs according to which the committee should function. • The IEC can refer to ICMR guidelines in preparing the SoPs for all biomedical and health research and to CDSCO guidelines for drug and device trials under the purview of the

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 31 licensing authority. The SOPs should be updated periodically to reflect changing requirements. A copy of the latest version of SOPs should be made available to each member and they should be trained on the SOPs. The SOPs must be available in the secretariat of the IEC as both hard and soft copies. The scope, tenure and renewal policy of the IEC should be stated. • Members of the IEC should not have any known record of misconduct.

3.2.4. Review Procedures The Ethics Committee should review every research proposal on human participants within reasonable period of time. It should ensure that a scientific evaluation has been completed before ethical review is taken up. The Committee should evaluate the possible risks to the participants with proper justification, the expected benefits and adequacy of documentation for ensuring privacy, confidentiality and justice issues. The ethical review should be done through formal meetings and should not resort to decisions through circulation of proposals.

3.2.5. Submission of Application The Investigator should submit an appropriate application to the IEC in a prescribed format along with the study protocol at least three weeks in advance. The application should include the following: • Clear research objectives and rationale for undertaking the investigation in human participants in the light of existing knowledge. • Recent curriculum vitae of the Investigators indicating qualification and experience. • Participant recruitment procedures. • Inclusion and exclusion criteria for entry of participants in the study. • Precise description of methodology of the proposed research, including intended dosages and routes of administration of drugs, planned duration of treatment and details of invasive procedures if any. • A description of plans to withdraw or withhold standard therapies in the course of research. • The plans for statistical analysis of the study. • Procedure for seeking and obtaining informed consent with sample of participant information sheet and informed consent forms in English and vernacular languages. • Safety of proposed intervention and any drug to be tested, including results of relevant laboratory and animal research.

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• For research carrying more than minimal risk, an account of plans to provide medical therapy for such risk or injury or toxicity due to over-dosage should be included. • Proposed compensation and reimbursement of incidental expenses. • Storage and maintenance of all data collected during the trial. • Plans for publication of results - positive or negative - while maintaining the privacy and confidentiality of the study participants. • A statement on probable ethical issues and steps taken to tackle the same. • All other relevant documents related to the study protocol including regulatory clearances. • Agreement to comply with national and international GCP protocols for clinical trials. • Details of Funding agency / Sponsors and fund allocation for the proposed work.

3.2.6. Decision Making Process The IEC should be able to provide complete and adequate review of the research proposals submitted to them (at least 1 week) to review the proposal and related documents, except in the case of expedited review. It should meet periodically at frequent intervals to review new proposals, evaluate annual progress of ongoing ones and assess final reports of all research activities involving human beings through a previously scheduled agenda, amended wherever appropriate. The decision must be taken by a broad consensus after the quorum requirements are fulfilled to recommend / reject / suggest modification for a repeat review or advice appropriate steps. The Member Secretary should communicate the decision in writing.

Types of the decision bv the TEC- An IEC can give one of the following decisions: • approved - with or without suggestions or comments; • revision with minor modifications/amendments — approval is given after examination by the Member Secretary or expedited review, as the case may be; • revision with major modifications for resubmission - this will be placed before the full committee for reconsideration for approval; or • Not approved (or termination/revoking of permission if applicable) - clearly defined reasons must be given for not approving/terminating/revoking o f permission. • A member must voluntarily withdraw from the IEC while making a decision on an application which evokes a conflict of interest which should be indicated in writing to the chairperson prior to the review and should be recorded so in the minutes.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 33 • If one of the members has her/his own proposal for review, then the member should not participate when the project is discussed. • A negative decision should always be supported by clearly defined reasons. • An IEC may decide to reverse its positive decision on a study in the event of receiving information that may adversely affect the benefit/risk ratio. • The discontinuation of a trial should be ordered if the IEC finds that the goals of the trial have already been achieved midway or unequivocal results are obtained. • In case of premature termination of study, notification should include the reasons for termination along with the summary of results conducted till date.

The following circumstances require the matter to be brought to the attention of IEC: • Any amendment to the protocol from the originally approved protocol with proper justification; • Serious and unexpected adverse events and remedial steps taken to tackle them; • Any new information that may influence the conduct of the study. • If necessary, the Applicant/Investigator may be invited to present the protocol or offer clarifications in the meeting. Representative of the participant groups or interest groups can be invited during deliberations to offer their viewpoint. • Subject Experts may be invited to offer their views, but should not take part in the decision making process. However, her/his opinion must be recorded. • Meetings are to be Minutes which should be approved and signed by the Chairperson.

3.2.7. Interim Review The IEC should decide and record the special circumstances and the mechanism when an interim review can be resorted-to instead of waiting for the scheduled time of the meeting. This can be done for the following reasons: i) Re-examination of a proposal already examined by the IEC; ii) Research study of a minor nature such as examination of case records etc.; iii) An urgent proposal of national interest.

3.2.8. Record Keeping • All documentation and communication of an IEC should be dated, filed and preserved according to written procedures. • Confidentiality should be maintained during access and retrieval procedures by designated persons.

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• All active and inactive (closed) files should be appropriately labelled and archived separately in designated areas. • Records can be maintained in hard copies as well as soft copies. • All records must be archived for a period of at least 3 years after the completion/ termination of the study. • Documents related to regulatory clinical trials must be archived for 5 years after the completion/termination of the study or as per regulations. • Records may be archived for a longer period, if required by the sponsors/regulatory Bodies • IEC should describe archival and retrieval mechanisms in SOPs. • IEC records should be accessible for inspection by authorized representatives of regulatory agencies.

3.2.9. Special Considerations While all the above requirements are applicable to Ayurvedic Medicine research as a whole irrespective of the specialty of research, there are certain specific concerns pertaining to specialized areas of research which require additional safeguards / protection and specific considerations for the IEC to take note of. Examples of such instances are research involving children, pregnant and lactating women, vulnerable participants and those with diminished autonomy besides issues pertaining to commercialization of research and international collaboration. The observations and suggestions of IEC should be given in writing in unambiguous terms in such instances.

3.3. Informed Consent Process The information should be given to the Participants and / or their legal representatives or guardians in a language and at a level of complexity that is understandable to the Participant(s) in both written and oral form, whenever possible.

The ICD has two parts - (i) patient/participant information sheet (PIS) and (ii) the informed consent form (ICF). Information on known facts about the research, which has relevance to participation, is included in the PIS. This is followed by the ICF in which the participant acknowledges that she/he has understood the information given in the PIS and is volunteering to be included in that research.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 35 3.3.1. Patient /Participant Information Sheet (PIS) Before requesting an individual’s consent to participate in research, the investigator must provide the individual with the following information in the language he or she is able to understand which should not only be scientifically accurate but should also be sensitive to their social and cultural context: • The aims and methods of the research; • The expected duration of the participant participation; • The benefits that might reasonably be expected as an outcome of research to the participant or to others; • Any alternative procedures or courses of treatment that might be as advantageous to the participant as the procedure or treatment to which she/he is being subjected; • Any foreseeable risk or discomfort to the participant resulting from participation in the study; • The extent to which confidentiality of records could be able to safeguard, confidentiality and the anticipated consequences of breach of confidentiality; • Free treatment for research related injury by the investigator / institution; • Compensation of participants for disability or death resulting from such injury; • Freedom of individual / family to participate and to withdraw from research any time without penalty or loss of benefits which the participant would otherwise be entitled to;

• The identity of the research teams and contact persons with address and phone numbers; • Foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research and if the material is likely to be used for secondary purposes or would be shared with others, clear mention of the same; • Risk of discovery of biologically sensitive information; • Publication, if any, including photographs and pedigree charts. • Information on standard of care (including modem medicine) The quality of the consent of certain social groups requires careful consideration as their agreement to volunteer may be unduly influenced by the Investigator.

3.3.2. Informed Consent form 3.3.2.I. Informed Consent of Participant Prior to the beginning of the Study the Investigators) must obtain the Ethics Committee’s approval for the written informed consent form and all information being provided to the

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Participants and / or their legal representatives or guardians or an impartial witness in case participant /Legally Authorized Representative (LAR) is illiterate. None of the oral and written information concerning the Study, including the written informed consent form, should contain any language that causes the Participant(s) or their legal representatives or guardians to waive or to appear to waive their legal rights, or that releases or appears to release the Investigator, the Institution, the Sponsor or their representatives from their liabilities for any negligence.

This requirement is based on the principle that competent individuals are entitled to choose freely whether or not to participate or continue to participate in the research. Informed consent is a continuous process involving three main components - providing relevant information to potential participants, ensuring competence of the individual, ensuring the information is easily comprehended by the participants and assuring voluntariness of participation.

Informed voluntary consent protects the individual’s freedom of choice and respects the individual’s autonomy. Requisites • The participant must have the capacity to understand the proposed research, be able to make an informed decision on whether or not to be enrolled and convey her/his decision to the researcher in order to give consent. • The consent should be given voluntarily and not be obtained under duress or coercion of any sort or by offering any undue inducements. • In the case of an individual who is not capable of giving voluntary informed consent, the consent of LAR must be obtained. • It is necessary to maintain privacy and confidentiality of participants at all stages

3.3.2.2. Informed Consent in Non-Therapeutic Study In case of a Non-Therapeutic study the consent must always be given by the participant. Non Therapeutic Studies may be conducted in participants with consent of a legal representative or guardian provided all of the following conditions are fulfilled: • The objective of the study cannot be met by means of a trial in Participants) who can personally give the informed consent • The foreseeable risks to the Participant(s) are low • Ethics Committee’s written approval is expressly sought on the inclusion of such Participant(s)

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 37 3.3.2.3. Community consent In certain populations, the community plays an important role in the consent process. Some participants may not participate in the research unless the community’s consent is available. There may be situations when individual consent cannot be obtained as it will change the behaviour of the individual. In such situations community consent is required. When permission is obtained from an organization that represents the community, the quorum required for such a committee must be met. For example, in a village panchayat the number of members ordinarily required to conduct a meeting must be present while giving consent. Individual consent is important and required even if the community gives permission.

3.3.2.4. Documentation of Informed Consent process • Each prospective participant should sign the informed consent form after going through the informed consent process of receiving information, understanding it and voluntarily agreeing to participate in the research. • In case the participant is incompetent (medically or legally) to give consent, the LAR’s consent must be documented. • The process of consent for an illiterate participant/LAR should be witnessed by an impartial literate witness who is not a relative of the participant and is in no way connected to the conduct of research, such as other patients in the ward who are not in the study, staff from the social service department and counsellors. The witness should be a literate person who can read the participant information sheet and consent form and understand the language of the participant. • If the participant cannot sign then a thumb impression must be obtained. • The researcher who administers the consent must also sign and date the consent form. • In the case of institutionalized individuals, in addition to individual/LAR consent, permission for conducting the research should be obtained from the head of that institution. • In some types of research, the partner/spouse may be required to give additional consent. • In genetic research, other member of a family may become involved as secondary participants if their details are recorded as a part of the family history. If information about the secondary participants is identifiable then their informed consent will also be required. • Online consent may be obtained, for example, in research involving sensitive data such as unsafe sex, high risk behaviour, use of contraceptives (condoms, oral pills), or emergency

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contraceptive pills among unmarried females in India etc. Investigators must ensure that privacy of the participant and confidentiality of related data is maintained.

3.3.2.5. Procedures after the consent process • After consent is obtained, the participant should be given a copy of the PIS and signed ICF unless the participant is unwilling to take these documents. Such reluctance should be recorded. • The researcher has an obligation to convey details of how confidentiality will be maintained to the participant. • The original PIS and ICF should be archived as per the requirements given in the guidelines and regulations.

3.4. Waiver of consent The researcher can apply to the IEC for a waiver of consent if the research involves less than minimal risk to participants and the waiver will not adversely affect the rights and welfare of the participants. Conditions for granting waiver of consent The IEC may grant consent waiver in the following situations: • research cannot practically be carried out without the waiver and the waiver is scientifically justified; • retrospective studies, where the participants are de-identified or cannot be contacted; • research on anonymized biological samples/data; • certain types of public health studies/surveillance programmes/programme evaluation studies; • research on data available in the public domain; or • research during humanitarian emergencies and disasters, when the participant may not be in a position to give consent. Attempt should be made to obtain the participant’s consent at the earliest.

3.5. Responsibilities of the Researcher • The researcher should only use the IEC approved version of the consent form, including its local translations. • Adequate information necessary for informed consent should be communicated in a language and manner easily understood by prospective participants.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 39 • In case of differently abled participants, such as individuals with physical, neurologicalor mental disabilities, appropriate methods should be used to enhance the participants’understanding, for example, braille for the visually impaired. • There should be no restriction on the participant’s right to ask questions related to the study or to discuss with family and friends or take time before coming to a decision. • The researcher should not give any unjustifiable assurances or influence or intimidatea prospective participant to enroll in the study. • The researcher must ensure that the participant is competent and has understood all aspects of the study and that the consent is given voluntarily. Where the participant and/or the LAR are illiterate, an impartial literate person, not connected to the research, should be present throughout the consent process as witness. • The researcher should administer a test of understanding whenever possible for sensitive studies. If need be, the test may be repeated until the participant has really understood the contents. • When a participant is willing to participate but not willing to sign or give a thumb impression or cannot do so, then verbal/oral consent may be taken on approval by the IEC, in the presence of an impartial witness who should sign and date the consen document. This process can be documented through audio or video recording of the participant, the PI and the impartial witness, all of whom should be seen in the frame.However, verbal/oral consent should only be taken in exceptional circumstances andfor specific, justifiable reasons with the approval of the IEC. It should not to be practiced routinely. • The researcher must assure prospective participants that their decision whether or notto participate in the research will not affect their rights, the patient-clinician relations hipor any other benefits to which they are entitled. • Reimbursement may be given for travel and incidental expenses/participation in research after approval by the IEC . • The researcher should ensure free treatment for research related injury (disability,chronic life-threatening disease and congenital anomaly or birth defect) and if required, payment o compensation over and above medical management by the investigator and/institution and sponsor(s), as the case may be. • The researcher should ensure that the participant can continue to access routine care even in the event of withdrawal of the participant.

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3.6. Responsibilities of the Institution for conducting a research in alliance with industries/commercial companies

Academic institutions conducting research in alliance with industries/commercial companies require a strong review to probe possible conflicts of interest between scientific responsibilities of Investigators and business interests (e.g. ownership or part ownership of a company developing a new product). In cases where the review board/committee determines that a conflict of interest may damage the scientific integrity of a study or cause harm to research participants, the board should advise accordingly. Institutions need self-regulatory processes to monitor, prevent and resolve such conflicts of interest. Prospective participants in research should also be informed of the sponsorship of research, so that they can be aware of the potential for conflicts of interest and commercial aspects of the research. Undue inducement through compensation for individual participants, families and populations should be prohibited. This prohibition however, does not include agreements with individuals, families, groups, communities or populations that foresee technology transfer, local training, joint ventures, provision of health care reimbursement, costs of travel and loss of wages and the possible use of a percentage of any royalties for humanitarian purposes.

3.7. Selection of Vulnerable groups as Research Participant The word vulnerability is derived from the Latin word vulnarere which means ‘to wound’. Vulnerable persons are those individuals who are relatively or absolutely incapable of protecting their own interests because of personal disability; environmental burdens; social injustice; lack of power, understanding or ability to communicate or are in a situation that prevents them from doing so. Vulnerable populations have an equal right to be included in research so that benefits accruing from the research apply to them as well. These vulnerable persons have some common characteristics which are listed below- • socially, economically or politically disadvantaged and therefore susceptible to being exploited; • incapable of making a voluntary informed decision for themselves or whose autonomy is compromised temporarily or permanently, for example people who are unconscious, differently abled; • able to give consent, but whose voluntariness or understanding is compromised due to their situational conditions; or • unduly influenced either by the expectation of benefits or fear of retaliation in case of refusal to participate which may lead them to give consent.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 41 Following are some examples of vulnerable populations or groups: • economically and socially disadvantaged (unemployed individuals, orphans, abandoned individuals, persons below the poverty line, ethnic minorities, sexual minorities - lesbian/ gay/bisexual and transgender (LGBT), etc.); • unduly influenced either by the expectation of benefits or fear of retaliation in case of refusal to participate which may lead them to give consent; • children (up to 18 years); • women in special situations (pregnant or lactating women, or those who have poor decision making powers/poor access to healthcare); • tribals and marginalized communities; • refugees, migrants, homeless, persons or populations in conflict zones, riot areas or disaster situations; • afflicted with mental illness and cognitively impaired individuals, differently abled - mentally and physically disabled; • terminally ill or are in search of new interventions having exhausted all therapies; • suffering from stigmatizing or rare diseases; or • have diminished autonomy due to dependency or being under a hierarchical system (students, employees, subordinates, defence services personnel, healthcare workers, institutionalized individuals, under trials and prisoners).

3.7.1. Pregnant or nursing women Pregnant or nursing women should in no circumstances be the participant of any research unless the research carries no more than minimal risk to the fetus or nursing infant and the object of the research is to obtain new knowledge about the foetus, pregnancy and lactation. As a general rule, pregnant or nursing women should not be participants of any clinical trial except such trials as are designed to protect or advance the health of pregnant or nursing women or foetuses or nursing infants, and for which women who are not pregnant or nursing would not be suitable participants.

The justification of participation of these women in clinical trials would be that they should not be deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines or other agents that promise therapeutic or preventive benefits. Example of such trials are- a. Test the efficacy and safety of a drug for reducing peri-natal transmission of HIV infection from mother to child

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The trials for detecting fetal abnormalities and for conditions associated with or aggravated by pregnancy, etc. Women should not be encouraged to discontinue nursing for the sake of participation in research and in case she decides to do so, harm of cessation of breast feeding to the nursing child should be properly assessed except in those studies where breast feeding is harmful to the infant. b. Research related to termination of pregnancy Pregnant women who desire to undergo Medical Termination of Pregnancy (MTP) could be made participants for such research as per the Medical Termination of Pregnancy Act, Government of India, 1971. c. Research related to pre-natal diagnostic techniques In pregnant women such research should be limited to detect the foetal abnormalities or genetic disorders as per the Prenatal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, GOI, 1994 and not for sex determination of the foetus.

3.7.2. Children Before undertaking trial in children below the age of 18 years the Investigator must ensure that - a. Children will not be involved in research that could be carried out equally well with adults; b. The purpose of the research is to obtain knowledge relevant to health needs of children. For clinical evaluation of a new Ayurvedic drug / Patent or Proprietary Medicines the study in children should always be carried out after the phase III clinical trials in adults. It can be studied earlier only if the Ayurvedic drug / Patent or Proprietary Medicines have a therapeutic value in a primary disease of the children; c. A parent or legal guardian of each child has given proxy consent; d. The Assent of the child should be obtained to the extent of the child’s capabilities such as in the case of mature minors, adolescents etc. Considerations for assent • There is no need to document assent for children below 7 years of age. • For children between 7 and 12 years, verbal/oral assent must be obtained in the presence of the parents/LAR and should be recorded. • For children between 12 and 18 years, written assent must be obtained. This assent form also has to be signed by the parents/LAR. • Adolescents may have the capacity to give consent like adults. However, as they have not attained the legal age to provide consent, it is termed as assent and the consent of the parents/LAR should be obtained. If the latter will affect the validity of the study,

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 43 waiver of consent from the relevant adult should be taken and recorded with the approval of the IEC, for example, in behavioural studies in IV drug users where parental consent may not be possible. e. Research should be conducted in settings in which the child and parent can obtain adequate medical and psychological support; f. Interventions intended to provide direct diagnostic, therapeutic or preventive benefit for the individual child participant must be justified in relation to anticipated risks involved in the study and anticipated benefits to society; g. The child’s refusal to participate in research must always be respected unless there is no medically acceptable alternative to the therapy provided/tested. The consent has to be obtained from parents/guardian; h. Interventions that are intended to provide therapeutic benefit are likely to be at least as advantageous to the individual child participant as any available alternative interventions; i. The risk presented by interventions not intended to benefit the individual child participant is low when compared to the importance of the knowledge that is to be gained.

4. Registration of clinical trial Clinical trials hold enormous potential for benefiting participants, improving therapeutic regimens and ensuring advancement in medical practice that is evidence based. Registration of trials will ensure transparency, accountability and accessibility of clinical trials.

The Clinical Trials Registry- India (CTRI) hosted at the ICMR’s National Institute of Medical Statistics (NIMS), is a free and online (www.ctri.nic.in) public record system for registration of clinical trials being conducted in India

Today, any Investigator who plans to conduct a trial involving human participants of any intervention such as drugs, surgical procedures, preventive measures, lifestyle modifications, devices, educational or behavioral treatment, rehabilitation strategies as well as trials being conducted in the purview of the Ministry of AYUSH (http://indianmedicine.nic.in/) is expected to register the trial in the CTRI before enrollment of the first participant. Trial registration involves public declaration and identification of trial Investigators, Sponsors, Interventions, Participant population, Trial site, etc. before the enrollment of the first participant. Submission of Ethics approval and Ministry of AYUSH approval (if applicable) is essential for trial registration in the CTRI. Multi-country trials, where India is a participating country, which have been registered in an international registry, are also expected to be registered in the CTRI.

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In the CTRI, details of Indian investigators, trial sites, Indian target sample size and date of enrollment are captured. After a trial is registered, investigators are expected to regularly update the trial status or other aspects as the case may be. After a trial is registered, all updates and changes will be recorded and available for public display.

Being a Primary Register of the International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/search/en/), registered trials are freely searchable both from the WHO’s search portal, the ICTRP as well as from the CTRI (www.ctri.nic.in).

5. Record Keeping and Data Handling The basic concept of record-keeping and handling of data is to record, store, transfer, and where necessary convert efficiently and accurately the information collected on the trial participant(s) into data that can be used to compile the Study Report.

5.1. Documentation All steps involved in data management should be documented in order to allow step-by step retrospective assessment of data quality and study performance for the purpose of audit following the SoPs facilitates documentation. Documentation of SoPs should include details of checklists and forms giving details of actions taken, dates and the individuals responsible, etc.

5.2. Corrections All corrections in the CRFs or any other study related documents should be made in a way that does not obscure the original entry. The correct data should be inserted with the reason for the correction if such a reason is not obvious. The corrections should carry the date and initials of the Investigator or the authorized person.

5.3. Electronic Data Processing For electronic data processing only authorized person should be allowed to enter or modify the data in the computer and there should be a recorded trail of the changes and deletions made. A security system should be set-up to prevent un-authorized access to the data. If data is altered during processing the alteration must be documented and the system should be validated. The systems should be designed to permit data changes in such a way that the data changes are documented and there is no deletion of data once it has been entered. A list of authorized persons who can make changes in the computer system should be maintained. Adequate backup of the data should be maintained.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 45 5.4. Validation of Electronic Data Processing Systems If trial data are entered directly into the computer there must always be an adequate safeguard to ensure validation including a signed and dated printout and backup records. Computerized systems - hardware as well as software - should be validated and a detailed description of their use be produced and kept up-to-date.

5.5. Language All written documents, information and other material used in the Study should be in a language that is clearly understood by all concerned (i.e. the Participants, paramedical staff, Monitors etc.)

5.6. Responsibilities of the Investigator Investigator should ensure that the observations and findings are recorded correctly and completely in the CRFs and signed by the responsible person(s) designated in the Protocol. Laboratory values with normal reference ranges should always be recorded on a CRF or enclosed with the CRF. Values outside the clinically accepted reference range or values that differ importantly from previous values must be evaluated and commented upon by the Investigator. Data other than that requested by the Protocol may appear on the CRF clearly marked as the additional findings and their significance described by the investigator. Units of measurement must always be stated and transformation of units must always be indicated and documented. In the medical records of the participant(s) it should be clearly indicated that the individual is participating in a clinical trial. The immediate transport facility should be provided to the study personnel to nearby hospital for medical referral.

5.7. Responsibilities of the Sponsor and the Monitor The sponsor must ensure that electronic data processing system conforms to the certain documented requirements for completeness, accuracy, reliability and consistent intended performance (i.e. validation). The Sponsor must maintain SoPs for using these systems.

The Monitor should take adequate measures to ensure that no data is overlooked. If the computer system automatically assigns any missing values - the fact should be clearly documented.

Sponsor should safeguard the blinding, if any, particularly during data entry and processing. The Sponsor should use an explicit Participant identification code that allows identification of all the data reported for each Participant. Ownership of the data and any transfer of the ownership of data should be documented and intimated to the concerned party (ies).

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6. Publication Policy A publication policy, if not addressed in a separate agreement, should be described in theprotocol.

7. Common Problems in Research Protocols Some of the common mistakes are: • Inadequate literature review or conducting a quick survey when a systematic review is needed. • Vague research question, this means the question is too broad or unanswerable, and needs to be focused. • Flawed research design: Do not select a study type that will not answer the question. Much time and effort will be wasted. Most research failures can be traced to the early planning stages. • A project is too ambitious than the research skills of Investigator or the institutional resources is not sufficient in the institution responsible for. • Too many research questions: lacks focus and not achievable in time • Inadequate number of participants to answer the question: Do not count on the IEC to alert the researcher about this problem, which poses no risk to participants, even though it wastes the time of willing volunteers. • Inappropriate plan for statistical analysis: The statistician is planning to use the wrong tests to look at the data. • Poorly written consent form: The IEC will send the consent form back for rewriting if not comprehensive and legally sound. • A budget inadequate for the project, or even too high. • Failure to reach consensus on all aspects of the protocol.

8. Final steps After the Research Protocol is written (and re written a few times), it should be reviewed by a “Critical Reader” may be colleague or peer. This will help to identify the problems with organization or in the grammar that may detract from the merits of the idea. If the “critical- reader” colleague is not research-sawy, especially in your area of investigation, it may be reviewed by an experienced investigator.

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9. References

1. Good clinical practice guidelines for clinical trials in Ayurveda, Siddha & Unani medicine (GCP-ASU), Published by Dept, of AYUSH, Ministry of Health & family welfare, Govt. Of India, New Delhi, March 2013.

2. Good Clinical Practice Guidelines, Central Drugs Standard Control Organization (CDSCO), Ministry of Health, Govt, of India.

3. Guidance for Industry on Submission of Clinical Trial Application for Evaluating Safety and Efficacy (General considerations for conducting Clinical Trial as per Drugs and Cosmetics Act 1940 and Rules 1945) Document No. - CT/71108, Version - 1.1, Central Drugs Standard Control Organization Ministry of Health, Govt, of India.

4. Ethical Guidelines for Biomedical Research on Human Participants, Published by Indian Council of Medical Research, New Delhi, 2017.

5. Pandey A, Aggarwal AR, Seth SD, Maulik, M, Bano R. Juneja A. Clinical Trials Registry India: Redefining the conduct of clinical trials. Indian J Cancer 2008; 45 (3): 79-82.

6. Pandey A, Aggarwal A, Maulik, M, Seth SD. Clinical trial registration gains momentum in India. Indian JM ed Res [Letter to Editor] 2009; 130: 85-86.

7. Pandey A, Aggarwal AR, Seth SD, Maulik, M. Clinical Trials Registry ^ India: Raising the veil. Natl Med J India [Letter to Editor]2010; 23 (3):187 -188.

8. Schulz KF, Chalmers I, Hayes RJ, Altman D. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled clinical trials. JAMA 1995; 273:408-12.

9. Jni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ 2001; 323: 42-6.

10. Altman DG, Schulz KF, Moher D for the CONSORT Group. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001; 134: 663-94.

11. International Committee of Medical Journal Editors (ICMJE). Uniform Requirements for Manuscripts Submitted to Biomedical Journals. Available at http://www.icmje.org.

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12. Indian Council of Medical Research. Ethical Guidelines for Biomedical Research on Human Participants. New Delhi: Indian Council of Medical Research, 2000

13. Bhushan Patwardhan , Ashok D. B.Vaidya , Mukund Chorghade and Swati P. Joshi, Reverse Pharmacology and Systems Approaches for Drug Discovery and Development Current Bioactive Compounds 2008, 4, 000-000

14. Kenneth F Schulz, David A Grimes, Generation of allocation sequences in randomised trials: chance, not choice. Lancet 2002; 359: 515-19

15. Rathai Rajagopalan, Priyadarshini M.Deodurg, Srikanth Overview of Randomized Controlled Trials. Asian J Pharm Clin Res, Vol 6, Issue 3, 2013, 32-38.

16. Ethical Guidelines, for Biomedical research on Human participants. Indian council of medical research. New Delhi, 2006. http://www.icmr.nic.in/ethicalguidelines.pdf

17. Kenneth F Schulz, David A Grimes. Allocation concealment in randomised trials: defending against Deciphering THE LANCET. Vol 359, February 16: 2002. .www. thelancet. com

18. ICH Guidance for Industry M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (April 1997)

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 49 10. Further Reading Materials 1. Sacks HS, Berrier, J, Reitman D, Ancona-Berk VA, Chalmers T. Meta-analyses of randomized controlled trials. New England Journal of Medicine 1987;316:450-

2. Sacks HS, Berrier, J, Reitman D, Ancona-Berk VA, Chalmers T. Meta-analyses of randomized controlled trials: and update. In : Balder WC, Mosteller F, eds. Medical Uses of Statistics, 2nd ed.pp427-442 Boston, MA: NEJM Books, 199

3. Sacks HS. Meta analyses of clinical trials. In: Perman IA, Rey J, eds.Clinical Trials in Infant Nutritional, Nesle Nutrition Workshop series, Vol. 40pp 85-99. Philadelphia, PA; Vevey/Lippincott-Raven Publishers, 1998

4. Lachman L et al. Quality control charts. In: The theory and practice of industrial pharmacy. Philadelphia, Lea & Fbiger, 1986: 817-824WHO Expert Committee on Specifications for Pharmaceutical Preparations: thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790) p.47.

5. Good manufacturing practices: guidelines on the validation of manufacturing processes. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization, 1996 (WHO Technical Report Series, No. 863) 80-96.

6. Lowe DA. Guide to international recommendations on names and symbols for quantities and on units of measurement. Geneva, World Health Organization, 1975.

7. The SI for the health professions. Geneva, World Health Organization, 1977.

8. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790) Annex 2, pp.34-47

9. Codex Alimentations Commission. Guide: Codex maximum limits for pesticide residues, Part 2 April 1992 Rome, Food and Agriculture Organization of the United Nations, 1992 (unpublished FAQ document CX/PR2-1992; available in hard copy and electronic format from FAQ).

10. International Consultative Group on Food Irradiation, Consultation on microbiological criteria for foods to be further processed including by irradiation. Geneva, World Health Organization, 1989; 21 (unpublished WHO document WHO/EHE/FOS/89.5; available on

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request from Office of Global and Integrated Environmental Health, World Health Organization, 1211 Geneva 27, Switzerland). 11. Anonymous,, Quality control methods for Medicinal plant materials, WHO, Geneva 1998 12. Anonymous, Guide lines for methodologies on research & evaluation of research of Traditional medicine, WHO, Geneva., 2000, 13. Anonymous, Ethical guidelines for biomedical research, ICMR, New Delhi, 2000 14. Ramachandra Reddy K, Bhaishajya kalpana vignanam Choukhamba publications Varanasi 1998, 15. Charaka, Charaka Samhita, Choukhamba Sanskrit Series, Varanasi. 1997 16. Susruta, Susruta Samhita, Chowkhamba Sanskrit Series, Varanasi. 1962 17. Sharangadhara, Sharangadhara samhita, Choukhamba publications, Varanasi. 1984 18. Vagbhata, Astanga hridaya, Choukhamba publications, Varanasi. 1992 19. Sharma P.V, Dravya guna vignana, Choukhamba publications, Varanasi. 1978 20. Sharma P.V, Dravya guna sutram, Choukhamba publications, Varanasi. 1994 21. Singh R.H., The Holistic principles of Ayurvedic Medicine Choukhamba publications, Varanasil998. 22. Bhavamishra, Bhavaprakasha, Choukhamba publications , Varanasi. 1998. 23. Bhagavan Dash, Fundamenatal principles of Ayurveda,Konark publications, 1989. 24. Dwarakanath C., Introduction to Kaya Chikitsa, Choukhamba publications, Varanasi. 1986. 25. Quality control methods. In: Remington: the science and practice of pharmacy, 19th ed. Easton, PA, MACK, 1995: 118-119. 26. The international pharmacopoeia, 3rd ed. Geneva, World Health Organization, Vol.l: General methods of analysis, 1979. Vol.2: Quality specifications, 1981. Vol. 3 Quality specifications, 1988; Vol. 4: Tests, methods and general requirements. Quality specifications for pharmaceutical substances, excipients, and dosage forms, 1994 27. Public health impact of pesticides used in agriculture. Geneva, World Health Organization, 1990.

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 51 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

ANNEXURE-I

RULE 158 (B) - GUIDELINES FOR ISSUE OF LICENSE WITH RESPECT TO AYURVEDA. SIDDHA OR UNANI DRUGS

I. (A). Ayurveda, Siddha Unani Medicines under, section 3 (a):-

Ayurveda, Siddha or Unani drugs includes all medicines intended for internal or external use for or in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, and manufactured exclusively in accordance with the formulae described in the authoritative books of Ayurvedic, Siddha and Unani Tibb system of medicine, as specified in the First Schedule;

(B). Patent or Proprietary medicine under section 3(h);

(i) In relation to Ayurvedic, Siddha and Unani Tibb system of medicine of all formulations containing only such ingredients mentioned in the formulae described in the authoritative books of Ayurveda, Siddha or Unani Tibb system of medicines specified in the First Schedule, but does not include a medicine which is administered by parenteral route and also a formulation included in the authoritative books as specified in clause (a);

(ii) Balya/Poshak/Muqawi/Unavuporutkal/positive health Promoter formulations having ingredients mentioned in books of First Schedule of the Drugs and Cosmetics Act and recommended for promotional and preventive health.

(iii) Saundarya Prasadak (Husane afza)/Azhagh-sadhan formulation having ingredients mentioned in Books of First Schedule of the Drugs and Cosmetics Act and recommended for oral, skin, hair and body care.

(iv) Aushadh Ghana (Medicinal plant extracts - dry/wet) extract obtained from plant mentioned in books of First Schedule of the Act including Aqueous or hydro-alcohol.

II. (A) For issue of licence to the medicine with respect to Ayurvedic, Siddha and Unani, the conditions relating to safety study and the experience or evidence of effectiveness shall be such as specified in columns (5) and (6) of the Table given below:-

S. Category Ingredient Indication Safety Experience/Evidence of No. (S) (s) study Effectiveness (1) (2) (3) (4) (5) (6) Published Proof of Literature Effectiveness 1. (A) As per text As per text Not Required Not Required

52 General Guidelines for Clinical Evaluation of Ayurvedic Interventions ■Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

Ayurveda, Siddha Required and Unani drugs, given in 158.B as referred in 3(a) 2. (B) As per text As per text Not Required Not Required Any change in Required dosage form of Ayurveda Siddha and Unani drugs as described in section 3(a) of the Drugs and Cosmetics Act, 1940 3. (C) As per text New Not If Required Ayurveda, Siddha Required Required and Unani drugs referred in 3(a) to be used for new indication

II. B. For issue of license with respect to patent or proprietary medicine. The conditions relating to Safety studies and experience or evidence of effectiveness shall be specified as follows:- S. Category Ingredient Indication Safety Experience/Evidence of No. (S) (■) study Effectiveness

(1) (2) (3) (4) (5) (6)

Published Proof of Literature Effectiveness

1. Patent or As per text Textual Not Of * Pilot study as per Proprietary rationale required Ingredients relevant protocol medicine for Ayurveda and Siddha and Unani drugs.

2. Ayurveda As per text Existing Required Required Required Siddha, Unani drug with any of the ingredients of Schedule E (1) of the Drugs and Cosmetics Act, 1940

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 53 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

(V). For issue of license with respect to medicine Aushadh Ghana [extract of medicinal plant (dry/wet)] S. Category Ingredient Indication Safety study Experience/Evidence of No. (S) (s) Effectiveness (1) (2) (3) (4) (5) (6) Published Proof of Literature Effectiveness 1. (A) Aqueous As per text As per text Not Required Not Not Required Required 2. (Al) Aqueous As per text New Not Required Not Required Indication Required 3. (B) Hydro- As per text As per text Not Required If Not Required Alcohol Required 4. (Bl) Hydro- As New Required If Required Alcohol specified Indication** Required 5. Other than As As specified Required If Required Hydro/ Hydro- specified Acute, Required Alcohol Chronic, Mutagenicity and Teratogenicity

* The standard protocol with also include concept of Anupan, Prakriti & Tridosh etc. published by Central Research Councils Ayurveda, Siddha, Unani and other Government/Research Bodies.

** New Indication means which is other than mentioned in 1st schedule books of Drugs & Cosmetics Act, 1940

54 General Guidelines for Clinical Evaluation of Ayurvedic Interventions ANNEXURE-II GAZETTE NOTIFICATION FOR PHYTOPHARMACEUTICAL DRUGS

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(j.S-.K. flB lH j.-—W lh'rcas j J v lt u f Oto ilIl's k i:I . i Li> iiinuiid llv U iii^-- and C H rrlin R uin, |JJS , was. p u b lished, j-- c-j■.|■_ irl lI by s ti'lu m 1 2 j n d i c c t i o o 3 3 o f Ibc D m ^ and CusrTjclKS A ct, l*K W 4 2 5 o l I M O ) , f i d : 1 ncti IkalK H i i> l t h e L i ■.i ■■ ■/j i i i i L is ; 4>r India, in Ilk 1 M in tin ' tif tleaJlh anil I jjiiiK W elfare [D epartm ent o f tJeoLlh jinJ J atn.ly W e I lurch mimh^T Cf.S.H “ChJtJE:h d.ikil die JJ* (t|..K r. 2 0 1 3 , t r i 1 be G iiseke o f India. iLxtrM ndinaiy. I'.in IJ. Seelies .1 ,

S lh M tfio n (IJ- iLirted the i l 1 fJcuih-T. 3 0 1 3 . ii.i iiiill’ objection* anJ ■.uqpf.liijns fiom all pciM iai likjcly li» t>j jO o-lcd

L l k T i ' h y Ihe lY ■ r-L1 die esjns j nif a perV kl o f furLy fi h-e du>s I kith ih i' daL? Lin vth icli life? ci'|ije-. o f i lie O ffic ia l G a /clte (if 1 h c s jiJ ru lifk u lio n m ere rLkJc available Li lIil! public;

AraJ whereas m pie* Df Ihe Crawlee w d K rriftde j.', ai I.iK Il 1 l . h I v - [Hjhlican Ihf i ’V ' n c lL lu r, 2 0 J 3 ;

And uhcncas, the objections arxl xu^^Aliiiau. rocci^vd from rlw [Hihlic

Si" . ' . . l l u r e f i i n , i n c i e r c L s e ilid- n c i n f e m e d b y s u c t i o n 1 2 and action A .1 of ihe D n i j v amL Cotmetii:!!

A d , 1 - 0 4 0 ( 2 3 of IQJiH. Ihd- Cdnlral Govdniiivni, aller o.iri-.ijll jlkin uilh Ihe Drugs Tectink'Al Ailu-w!ty EtiunJ, h e u K makd-i thd follDwLng. julrs 11111:il-r ri» ..iivml Ihd D t u ^ a a n d O n s m r i L c * Riile -. I 'Ml'. r. iiiwlv

1. ( I j The-vc rules n u y he calk'd Ihc D r u f \ ^ n J 'Tihimcl'ics 4 Fifflrih Amcnilmcrrt.i Rules, 2thlS.

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60 The Gazette of India S JS -3 3 J G -3 _l l i g il I < j I : ii v l | ll ^ p »;i ll 7. = si in "S J c It il *-M J | a S* i i J I 5 & i s B .= if- ™ 3 1 1 fi e* m IIIn ^ U s5 f a a - ■“ * 1 31 if 11Jl ■s ■s L. g it7 a_. 1 111 3 1; I J f £¥■3 !1 i l l 4 j 11 5 1 i 11 J | 2 * " M 5 £/** ■a**h £ js Is *Eri* j i t s iiHi * i.& I s - a 3 S i u * s x s r* CL g t C S E s » ■ 1 1 - s j . -% * : i s “J II ■ &5 il&2 l l j ! it!£ a s ■eirfi'3 ■e'EE'a .£ 3 ? >- a £ £ a I 111!fill II f J i £ H ir! -J s>£ 3 _ 1 *" K - c S 3 ft THE-- liA/>1li: (IF I\TJ1A HKTHAlflHnrNAHV IPJt-HTlI— SH -. 3<0]

,1-}! Mtirpholisjjkeil jm l ; injHwnnr.il desvcripiMm ^ ih 11s_l; du-giiO'tie te.ilure-. :ind u ji|>tl(ifirj(ih si i ihe pljm or plaul purr Tar lurih.r Lm ifiniininmul identity u iJ aiuhenlK'iiy. iFuTii-.h-'.v.-nbliejLe i»f^LHitlFnimtiLMihoiuniL'uk identity hy a ■qualified Id U H w m i'li

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.V1) . An unde ruling <4h supply s]>eeiinfn Minpie uf pl.iin duly labeled and phutaneupy uf Lhe -Luriifimbe uf identify ronlirmuhiifi issued by a i|iuli[inl taxommiil jli'iiy wiili J m 1-'-miv ■■ or phokijjrapflis «T I)k dp^nnslkr nturpbotoskai nnJ In-'-iok'^K.il [calms of Lhc bcDuikal row mahiiaf uwd fotf llie M flflm ihn of aulhrnlrc iljr. J. PriiTt'-' Nir (i|r;ic■ Milnftiiif 111 TnditinuiLloii ;unI purifk>nlii>fi>; 4.1 Qvalii;r I1 lrtclhuth lur tiinimjj okUH-ful.

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(d) illTOftlUlKHt'Uff uny C.vCif>irtTiC> diFucn/lsof 'l-jfculivr ur pi-rvirivflivi- u m l. if aity.

J|.3. lV la ik i-.! |MeiK..pni”; i'I Ipiiril'ieJ Jind L'luurtL'riM.id. Hnal r■ i ■ 11. i. sLorugr ^>ndilH>riv. m il laht'hn^

62 The Gazette of India I H IT i l - w ^ M ill 60 tttt: : ™ ™ 9

S. FitrniiiljLlan .4 ptih iHiphiirmumjliL'ul drii^ up-plkd H i t :

5.1. D rluih N IK- L-i-ii-iH^ili.in. pM ffltkHI uf Ah1 I" n-il pun hod fnnl^vi vliMi defined iiuikiirs o \ |ihi inplmrrii.iiioliL.il drug per mill nmiic und pmpuriions ul nil Lwipknls. sluhiliwr' jnd any-fritter je c i:l u ^ d iii i.l ’ i;iL'kj L'i:ijj inalerials.

S.3. Tcsl fL\r idenii licaliuri for lhc pli>Icjihanruoeuti-jJ j J j uu

S. 1. (Jiu liE y 'p rc ifU v ilM im fa r i.lL v u Lind i i i 11 ■■ l |1 t i L . ■ |' I i ; i r n i . i l' ■/ >j i i ■_ j I ■_ I i r ■■ i ii : i ■■ l- r. i p 11 .=_■ (irpci piiii: pm llk ih |:h;.iih.Kr-iiiIl.iL refe nerkjt marker j.rnl assi\ nf activetHm'Jiiii*ni hiteharacienuic '. In'in .il iiurker.

f,. Muinlf*|-[liflilj- p n » W (rffHrfTOtJdllikni

4-1 I h owiirw sf (he mcttKx) of um w fjt!m t

fi S. D o Ih I^ 111 all partugiHJJ Hlatffiah U 'id. JVitiiitg ■«[* ^ Jfhl ikacrtpdoa of I hr filial

6-..1. Finished pmtfui'L's qujlith spn'ifk'jlHMls- iiVlmJin-j: Icsl* spn'ific fur Lhc dusjgr Ini in. i|ualily .umJ c4troivuno£f^p4iic liujii pfini pPuliltf *iJi ptyttwheinkal rtfertra iiwKer -aikJ tnaty to u lb t ronMifiUHii iw rfiaratlKiislii: irurker. if LKlm'c consliI■.hl ■ i■/. j i c nul V ik iv i.i i .

T. Stability data:

7. t . S io b ililj data i>l"(he p in h >|ihui in js cu lie j ! iCiug described ad >1 atwfvc, slored j .1 rw im temperature Jtl 4-11' *y. 2 d c & C . and humidiLy at 7 JK E H +.'- SS R It for Q, ln 2, 3 and * iramlhv

7 .2 S.ijH.11ic■, daLa nrf" Ihe ptiyh|)tuTnuce-ulical drug in iln-_i£e fiyrm it ftHTnularidn -.L'reil aL roam K nipcr.il .ire j f l(i + i- 2 dcp. ( ' anil hnm 'diiy at 7S%RI[ +.'■ fl'kR.I! Jivr 0, 1,2, .1 and ft months, in 1hc pact Lnie-niied fnr ncirktitng.

N, AH(I |lhjrrtUViilligtf-ijl I IlfEithlurlciih!:

K. I, liii.i on ufcty and ptHniBHifc>f}ul nwiie* m- hf prm idfd

n J, Anm vl Hwmny ;nm ^ friy nUna1

la I 2 lf Iii W d a ^ h repeal iSmc utfal h v iim ly v n !+ ’J s J t c L n ul anim al*.

11*4 /ji ■ivIa-i fcmvkiT. .'Mi dala-lAnKr's InL ajid (.lm iniuHiirul ahrrraliLvn t l ■-1. as perM 'jlm lulc V k

IfJ drrmnl liixxitjr Ir^s ftir ( l.j ik t j I |inxlLKls:

I d k 1l i.iI' iye ni'. il y \ lu d y I mil y i f p li^luph iH inaecuLk:all diu^r is i ik- u led fn r u’-c d a rin g j;ra ml /- ),

'f. 11 Iji n.Lih ..1 Mil Il ‘ 1

').]. nuiic.nl rri.il-- ^ir jihyKiph.irnftiijfiKkMl dnt^« in h r cntriiicied .i-s per npjilirnhL: nilcx am i _niiiik lirii'\ f-rr new dru^g*.

Q..2. R tr j .11 pMyri'jilLi'iiiiL'eiilhr.il ilni^-s dal.i Itmii: phau [ i.tih ileirnnirie nLiximum Hileraled dixtf jixL a'L\ocii1f J ifis;ici(k^) flnd (Ik ^Ih II I k ^ubi«i(iefl pnof no ppfw im m j iht

lJ 1 J.iia ni j^ l Ii-* (if d «n t fi nil ii: r -tnutifi. perfnf msit .md i Ih- p m i K n U h. ■ II he ^iihni iiif il p r u v in [Krfonnin^ llw

Pl'uvkkd ihn III Ilk i H of ptiyfu^tw ilUnjLkuL ilc^K aJrtadj- Wki/trtcd rur nuuc ihan fii-T ;► 5T-JI^ ni n- liLTe llx-ii- h Jilniunk (Hitlis'hcJ tu ljtM rc^iiidnip [Tk daftly Of [he filhyiupliainiai L ^ K -jl '.Ii ij.c. lhc 'I ndu s may It jW irfiH lcd. iikkJiIh J nr irljsril

HL t'onfiriM it-'r' cllniL iil Irin lY :

tO.l. SuhmiE pnihieols fnr a|'|■ r .11 Chit any specific nr sp^ial ufcL^ jnJetflcoLy sludy pnipt>Kd '.pcvifh; la Ihe phy4n[ihxnnKy:ul:iLaL dEU^

tn.2. Submit prapavd pmhienl for jpprm al for hunun clinica.1 Mudie-i appnyprule bn generate or vjlidabe Hiferj and eftkjey iL l ij for ihe phyInpharmaoeutical il'.'-jL’e fnrm ijt produrl « per apfilicable rules and guidelines.

1 Ij V uh in ii inrorm aLiiM i nn. hi^w Ihe itujliLy- n f ihe f i'in iu L ik 'n v. i -ulnl tic n u i nLtined d iu in j; Ihe a lx iw i t u d k f .

The Gazette of India 63 Id TIIF' CiATTTTF f)F INDIA : nXTRADRIANAR Y 1PAHTII -BET. 3Q)]

IL h.L'n.iiJulflrr ^latiu: N.I. Sijiiu of ihe [ihn1nplinrmjccLHL£^J drup nLLifccbed in any caunlry under any csiu^orj' like functional fivnl or dieury {iqipkmcrai a a& Indiiinnj] niL'ilieiru1 or :is in jpprfivid lItu p I2r .''lMrtiilirtK infuiJffl»1iuii:

] 2 . 1 LlrljiK flf pueMgr: in .'.IL tn puticiH inluiirM l^Ti J irrli »1 Ih e i+ i y l o p l u n n ->>.■ ■:■.11Tt-.11 druu !■:>be ii+irl.-rh.i.l

12.2 . Dr-ili uf Lhc ]ur liS;l .iiiil eaikut

IJ. I>i-1 miirkiel ii|: huntllbnre [ibMS |c

1 4.]. The upfilkuru idiaLI lurn.i-.ti periixJtr ofe*} update rcpticu every six nk-irlis far lhc rtrit twi> yc jjr, jfe r UPJKUVUL ih.' itflhJ. ia |^Jj.MKlI

I > 7. Pw i*v iht jKFwdk

1J . Anjr athrr rdrhunl iufHirnutlHin:

Aiv, >iii Jilt re k". anl infiw nuiitin v- hieh i Ik- j pplk ,-anl cofuida!! rkn il v. ill help i n sck; m ilk uv jlu.itii.in hi I' Ibc jpplK-BlMic.".

|F. No. X. 1101*30012-DFOCI

K. L. KHAHM A. JLSixy.

> iilil: Hie p u r.ip J rules were published in Ihe Gmetle uf libdia vide nohlieuEiun N.i, [\2Ji-LtL'45-I| {If duled Ihe 2 1 *1 Uix-emher. I 'W5 arxl m i laM j:i:enJed 1 hit n 1 :i I:.l j I n ri nu m ber Li S R H26 J li I. da lvd (he 3Chh G eU ibcr, 21)1 j .

E'l iiiIl'J liy 1||L- M .i Lii/L-1. 4 F ^L'l :iiih. IiI a i [b dlu Ih l ■ ■■. hl-S,- KirtmJ. MjI-i|Kji 1. Nl-'J, I \ ;i ■ I |i ■ V4 Jrtj l*lll*dwdly IhL- 4 'inilEii' kf 4ir PliMkilKUU, LV.Iii- 1 I' KH J.

64 The Gazette of India ■Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

ANNEXURE-III

LEVELS OF EVIDENCE The degree of importance of evidence is given in ascending order. For eg., Ia is considered to be highest level of evidence. Level Type of evidence

Ia Evidence obtained from meta-analysis of randomized controlled trials

lb Evidence obtained from at least one randomized controlled trial Ha Evidence obtained from at least one well-designed controlled study without randomization lib Evidence obtained from at least one other type of well-designed quasi-experimental study III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

Grading of recommendations: available criteria for recommendation of AYUSH intervention based on the level of evidences is given below. For e.g., availability of requirements as listed in Grade A gives a highest recommendation for the use of AYUH intervention.

Grade Recommendation A (Evidence levels quality Ia, lb) Requires at least one randomized controlled trial as part of the body of literature of overall good and consistency addressing the specific recommendation. B (Evidence levels Ha, lib, III) Requires availability of well-conducted clinical studies but no randomized clinical trials on the topic of recommendation. C (Evidence level IV) Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality.

Source: http://apps.who.int/medicinedocs/en/d/Jwhozip42e/6.3.html

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 65 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

ANNEXURE-IV

TEMPLATE FOR MONITORING

DURING VISIT OF MONITORING TEAM

Name of the Institute 1. Date of Visit of 2. Monitoring Team

Category of the project 3. (IMR / Collaborative)

4. Title of the Project Name of the Principal 5. Investigator

Name of the Co - 6. investigator(s)

Collaborator (If 7. applicable)

Budget sanctioned and 8. date of sanction

No. of Installment received with amount and 9. status of utilization (head wise)

Date of 10. Initiation/Enrollment

Status of IEC /IAEC 11. clearance

Status of CTRI 12. Registration /CTRI Registration No:

OPD Register (Random 13. checking of entries enrolled participants)

6 6 General Guidelines for Clinical Evaluation of Ayurvedic Interventions ■Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

14. Status of Execution

15. CRFs in Original(random c lecking) Randomly selected clinical /demographical information /investigations to be cross verified in CRFs & E-format/ Original reports

Current stock /Whether trial drug is present in 16. sufficient quantity

Storage conditions of trial 17. drugs

Registers/files / receipts (technical/drug/accounts, 18. etc) related to clinical / Pharmacological trial

Any other information 19. Expected period of 20. completion of targets

At the time of monitoring 21. the targets achieved as per deliverables\

Investigators/Head Signature Date Name of Signature Date of institute monitoring committee PI Co-PI Head of the Institute

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 67 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

ANNEXURE-V

DATA AND SAFETY MONITORING BOARD (DSMB) GUIDELINES

I. Roles and Responsibilities The Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises NIDCR and the study investigators. The members of the DSMB serve in an individual capacity and provide their expertise and recommendations. The primary responsibilities of the DSMB are to 1) periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy, and 2) make recommendations to NIDCR concerning the continuation, modification, or termination of the trial. The DSMB considers study-specific data as well as relevant background knowledge about the disease, test agent, or patient population under study.

The DSMB is responsible for defining its deliberative processes, including event triggers that would call for an unscheduled review, stopping guidelines, unmasking (unblinding) and voting procedures prior to initiating any data review. The DSMB is also responsible for maintaining the confidentiality of its internal discussions and activities as well as the contents of reports provided to it. The DSMB should review each protocol for any major concern prior to implementation. During the trial, the DSMB should review cumulative study data to evaluate safety, study conduct, and scientific validity and integrity of the trial. As part of this responsibility, DSMB members must be satisfied that the timeliness, completeness, and accuracy of the data submitted to them for review are sufficient for evaluation of the safety and welfare of study participants. The DSMB should also assess the performance of overall study operations and any other relevant issues, as necessary.

Items reviewed by the DSMB include: • Interim/cumulative data for evidence of study-related adverse events; • Interim/cumulative data for evidence of efficacy according to pre-established statistical guidelines, if appropriate; • Data quality, completeness, and timeliness; Performance of individual centers; • Adequacy of compliance with goals for recruitment and retention, including those related to theparticipation of women and minorities; • Adherence to the protocol; • Factors that might affect the study outcome or compromise the confidentiality of the trial data (such asprotocol violations, unmasking, etc.); and, • Factors external to the study such as scientific or therapeutic developments that may impact participantsafety or the ethics of the study.

The DSMB should conclude each review with their recommendations to NIDCR as to whether the study should continue without change, be modified, or terminated. Recommendations regarding modification of the design and conduct of the study could include: • Modifications of the study protocol based upon the review of the safety data; • Suspension or early termination of the study or of one or more study arms because of serious concemsabout subjects’ safety, inadequate performance or rate of enrollment; • Suspension or early termination of the study or of one or more study arms because study objectiveshave been obtained according to pre-established statistical guidelines; • Optional approaches for NIDCR and investigators to consider when the DSMB determines that the incidence of primary study outcomes is substantially less than

6 8 General Guidelines for Clinical Evaluation of Ayurvedic Interventions ■Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

expected such as recommendations toincrease the number of trial centers or extend the recruitment period; and, • Corrective actions regarding a study center whose performance appears unsatisfactory or suspicious. Confidentiality must always be maintained during all phases of DSMB review and deliberations. Usually, only voting members of the DSMB should have access to interim analyses of outcome data by treatment group. Exceptions may be made when the DSMB deems it appropriate. The reason and to whom the exceptions for access to interim analyses is granted will be documented in the Closed Session Report. DSMB members must maintain strict confidentiality concerning all privileged trial results ever provided to them. The DSMB should review data only by masked study group (such as X vs. Y rather than experimental vs. control) unless or until the DSMB determines that the identities of the groups are necessary for their decision-making. Whenever masked data are presented to the DSMB, the key to the group coding must be available for immediate unmasking.

II. Membership The membership of the DSMB should reflect the disciplines and medical and dental specialties necessary to interpret the data from the clinical trial and to fully evaluate participant safety. The number of DSMB members depends on the phase of the trial, range of medical issues, complexity in design and analysis, and potential level of risk but generally consists of three to seven members including, at a minimum: • Expert(s) in the clinical aspects of the disease/patient population being studied; • One or more biostatisticians; and, • Investigators with expertise in current clinical trials conduct and methodology. Ad hoc specialists may be invited to participate as non-voting members at any time if additional expertise is desired. Some trials, depending on the population and nature of the intervention, may well be served by inclusion of a bioethicist on the DSMB, Steering Committee, or Advisory Panel. NIDCR staff without direct involvement in study implementation and who meet other membership criteria may participate as ex officio, non-voting members. NIDCR staff serving in these positions must have a current confidential financial disclosure report on file with the Deputy Ethics Counselor, NIDCR. Representatives of the manufacturer (industrial collaborator) of the test substance(s) or any other individual with vested interests in the outcome of the study are not eligible to serve on the DSMB although they may attend open sessions of the DSMB meetings.

Conflict o f Interest No member of the D SMB should have direct involvement in the conduct of the study. Furthermore, no member should have financial, proprietary, professional, or other interests that may affect impartial, independent decision-making by the DSMB. Letters of invitation to prospective DSMB and ad hoc members should include the following: "Acceptance of this invitation to serve on the xxx DSMB confirms that I do not have any financial or other interest with any of the collaborating or competing pharmaceutical firms or other organizations involved in the study that constitute a potential conflict of interest." In addition, all DSMB and ad hoc members will sign a Conflict of Interest certification to that effect at the time they are asked to participate . At the beginning of every DSMB meeting, NIDCR program staff or the DSMB Chair will reconfirm that no conflict of interest exists for DSMB members. Interests that may create a potential conflict of interest should be disclosed to the DSMB prior to any discussion. The DSMB will determine how to handle such potential conflict. The DSMB can require that a member with a potential conflict not vote or take other means deemed appropriate. NIDCR may

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 69 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll dismiss a member of the DSMB in the event of unmanageable potential conflict or appearance of conflict.

Selection and Invitation to Participate The Program Official (PO) holds prima ry responsibility for the formation of the DSMB unless the Clinical Terms of Award for a grant or the Roles and Responsibilities negotiated for a protocol specifically identify this as the responsibility of the grantee. The PO (or grantee as specified) is responsible for developing the roster of potential DSMB members. Recommendations for proposed members are solicited from many sources. Study investigators and the industrial collaborators should have the opportunity to review the list of proposed members before the candidate’s interest and availability are confirmed by the PO (or grantee as specified). The proposed roster of members must be submitted to the Director, Office of Clinical Trials.

When is a DSMB Needed? A DSMB is indicated, from a practical perspective in the following circumstances: • If the trial is intended to provide definitive information about effectiveness and/or safety of a medical or biobehavioral intervention • If there are prior data to suggest that the intervention being studied has the potential to induce potentially unacceptable toxicity • If the trial is evaluating mortality or another major endpoint, such that inferiority of one treatment arm has safety as well as effectiveness implications • If it would ethically be important for the trial to stop early if the primary question addressed has been definitively answered, even if secondary questions or complete safety information were not yet fully addressed.

It is generally expected that a DSMB will be utilized in the following situations: • All Phase III studies require a DSMB, with the exception of low-risk behavioral and nutritional studies. o For this discussion, "low-risk" refers to trials where subjects are expected to experience only minor sideeffects, and interim analyses are not crucial for the protection of the subjects o The involvement of a DSMB may still be requested for low-risk studies if the studies are exceptionally large,long term, and/or involve vulnerable subjects • Phase II clinical trials which are multicenter and randomized require a DSMB, with the exception of low-riskbehavioral and nutritional studies • Phase II studies which are "high risk" require a DSMB o For this discussion, "high-risk" refers to trials of interventions associated with substantial side effects tosubjects (e.g., side effects that could result in serious morbidity or death, or are irreversible), trials ofdiseases associated with high mortality or morbidity, and trials of highly experimental therapies (e.g., genetherapy) o As a general guideline, DSMBs are needed for clinical trials of diseases with high mortality or morbidity, forclinical trials involving high risks, and for large, multicenter clinical trials • For some studies involving particularly vulnerable study participants (e.g., children or persons with impairedability to consent), it may be beneficially to utilize a DSMB as an additional measure of subject protection

A DSMB is NOT generally expected in the following situations:

70 General Guidelines for Clinical Evaluation of Ayurvedic Interventions Ill I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I IN I I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I I III I IN I

• Single-center open-label Phase I and II clinical trials generally do not need a DSMB since the local investigatorwill have access to all data. In these types of trials, the investigator could appoint an independent medicalmonitor to evaluate adverse events and make recommendations for continuing or stopping a trial • A multicenter, high-risk Phase I clinical trial should not require a DSMB if there are very clear rules for stoppingthe trial. For example, a DSMB is generally not required for a classic open-label dose escalation trial with clearand objective criteria for halting the dose escalation when unacceptable side effects are observed.A DSMB is likely to be requested if the DSMP lacks objective criteria for continuing or halting the trial • A DSMB may not be feasible for clinical trials that are expected to accrue too quickly to allow for a DSMB to be constituted and complete data and safety monitoring

NIH or other Federal Grants • If you are considering utilizing the NC TraCS DSMB to monitor a clinical trial included in an NIH or federal grant,please submit a copy of your grant to the DSMB for review in advance of submitting the grant to the agency.The DSMB prefers to review research proposals prior to submission to a funding agency in order to determinewhether the NC TraCS DSMB is the appropriate body to monitor the study • The NC TraCS DSMB will provide guidance to the investigator regarding study stopping rules, appropriate studydesign, and the safety monitoring plan. If the TraCS DSMB agrees to provide oversight for the clinical trial, aletter of support will be written that describes the DSMB and their role in monitoring the study • A copy of the NC TraCS DSMB Charter to be included with the grant application will be provided upon request. Please note that all NIH funded clinical trials require a Data and Safety Monitoring PLAN; however, only someclinical trials require a Data and Safety Monitoring BOARD. • Data and Safety Monitoring Boards (DSMBs) are specifically required for multi-site clinical trials with interventions that entail risk(s) to participants • DSMBs are generally required for Phase III clinical trials • A DSMB may be required for Phase I, Phase II or Phase III clinical trials if: o The clinical trial is blinded o The clinical trial involves high risk intervention(s), or o The clinical trial includes vulnerable population(s)

Source: [National Institutes o f Health (NIH) & National Institute o f Dental and Craniofacial Research (NIDCR)]

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 71 Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

ANNEXURE-VI

LIST OF SoPs

1. Writing, Reviewing, Distributing and Amending Standard Operating Procedures for IECs 2. Constituting an Ethics Committee 3. Confidentiality Agreements 4. Conflict of Interest Agreements 5. Training Personnel and EC Members 6. Selection of Independent Consultants 7. Procedures for Allowing a Guest or Observer 8. Categorization of Submitted Protocols for Ethics Review a. Initial Full Committee Review of New Research Protocols b. Expedited Review of Research Protocols c. cExemption from Ethics Review of Research Protocols 9. Agenda Preparation, Meeting Procedures and Minutes 10. Review of New Medical Device Studies 11. Review of Resubmitted Protocols 12. Review of Protocol Amendments 13. Continuing Review of Protocols 14. Review of Final Reports 15. Review of Serious Adverse Events (SAE) Reports 16. Review of Study Completion Reports 17. Management of Premature Termination, Suspension, Discontinuation of the Study 18. Waiver of Written or Verbal/oral Informed Consent 19. Site Monitoring Visits 20. Dealing with Participants’ Requests and Complaints 21. Emergency Meetings 22. Communication Records 23. Maintenance of Active Study Files 24. Archive and Retrieval of Documents 25. Maintaining Confidentiality of EC’s Documents 26. Reviewing Proposals involving Vulnerable Populations 27. Review and Inspection of the EC 28. Audio Visual Recording of the Informed Consent Process

72 General Guidelines for Clinical Evaluation of Ayurvedic Interventions 1 IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I IN I I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I I III I IN I

ANNEXURE-VII

ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL

Introduction

Essential Documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements. Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor, and monitor. These documents are also the ones that are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. The minimum list of essential documents that has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated (1) before the clinical phase of the trial commences, (2) during the clinical conduct of the trial, and (3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable. Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files. Any or all of the documents addressed in this guidance may be subject to, and should be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies). A. Before the Clinical Phase of the Trial Commences

During this planning stage the following documents should be generated and should be on file before the trial formally starts.

SI. Title of Document Purpose Located in Files of No Investigator Sponsor Institution 1. Investigator’s brochure To document that relevant and XX current scientific information about the investigational product has been provided to the investigator 2. Signed protocol and To document investigator and XX amendments, if any, and sponsor agreement to the sample case report form protocol/amendment(s) and (CRF) CRF 3. Information given to trial XX subject:

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 73 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

- Informed consent form To document the informed (Including all applicable consent translations) -Any other written To document that subjects will information be given appropriate written information (content and X X wording) to support their ability to give fully informed consent -Advertisement for subject recruitment (if used) To document that recruitment X measures are appropriate and not coercive

4 Financial aspects of the trial To document the financial XX agreement between the investigator/ institution and the sponsor for the trial 5 Insurance statement To document that XX (wherever required) compensation to subject(s) for trial-related injury will be available 6 Signed agreement between To document agreements involved parties, e.g.: - Investigator/institution and X X sponsor - Investigator/institution and X X CRO (where required) - Sponsor and CRO - Investigator/institution and X X authority(ies) (Where required) X 7 Dated, documented To document that the trial has XX approval/favorable opinion been subject to IRB/IEC of IRB/IEC of the review and given following: approval/favorable opinion. -Protocol and any To identify the version number amendments and date of the documents). - CRF (if applicable) - Informed consent form(s) -Any other written information to be provided to the subject(s) - Advertisement for subject recruitment (if used) - Subject compensation (if any) -Any other documents givenapproval/favorable opinion

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8 Institutional review board To document that the IRB/IEC XX /Institutional Ethics is constituted in agreement (where Committee composition with GCP required) 9 Regulatory authority(ies) To document appropriate X X authorization/ approval/ authorization/approval/ (where (where notification of protocol notification by the regulatory required) required) (where required) authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable regulatory requirement(s) 10 Curriculum vitae and/or To document qualifications XX other relevant documents and eligibility to conduct trial evidencing qualifications of and/or provide medical investigator(s) and supervision of subjects subinvestigators 11 Normal value(s)/range(s) for To document normal values XX medical/laboratory/technical and/or ranges of the tests procedure(s) and/or test(s) included in the protocol 12 Medical/laboratory/technical To document competence of X X procedures/tests facility to perform required (where test(s), and support reliability required) - Certification or of results - Accreditation or - Established quality control and/or external quality assessment or - Other validation (where required) 13 Sample of label(s) attached To document compliance with X to investigational product applicable labeling regulations container(s) andappropriateness of instructions provided to the subjects 14 Instructions for handling of To document instructions XX investigational product(s) needed to ensure proper and trial- related materials storage, packaging, dispensing, (if not included in protocol and disposition of or Investigator’s Brochure) investigational products and trial-related materials 15 Shipping records for To document shipment dates, XX investigational product(s) batch numbers, and method of and trial-related materials shipment of investigational product(s) and trial related materials. Allows tracking of product batch, review of shipping conditions, and accountability. 16 Certificate(s) of analysis of To document identity, purity X investigational product(s) and strength of investigational

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shipped products to be used in the trial. 17 Decoding procedures for To document how, in case of XX blinded trials an emergency, identity of (Third blinded investigational party if product can be revealed applic without breaking the blind for able) the remaining subjects’ treatment 18 Master randomization list To document method for X randomization of trial (Third population party if applicable) 19 Pretrial monitoring report To document that the site is X suitable for the trial (may be combined with point no.20) 20 Trial initiation monitoring To document that trial XX report procedures were reviewed with the investigator and investigator’s trial staff (may be combined with point no. 19)

B. During the Clinical conduct of the Trial

In addition to having on file the above documents, the following should be added to thefiles during the trial as evidence that all new relevant information is documented as itbecomes available.

Title of Document Purpose Located in Files of

Investig Sponsorlnstitution ator 1 Investigator’s Brochure To document that XX updates investigator is informed in a timely manner of relevantinformation as it becomes available 2 Any revisions to: To document revisions of XX these trial- related documents - Protocol/amendment(s) and that take effect during trial CRF - Informed consent form 3 Dated, documented To document that the XX approval/favorable opinion of amendment(s) and/or institutional review board revision(s) have been subject (IRB)/ Institutional Ethics to IRB/IEC review and were Committee (IEC) of the given approval/favorable following: opinion. To identify the version number and date of -Protocol amendment(s) the document(s) Revision(s) of:

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- Informed consent form Any other written information to beprovided to the subject - Advertisement for subject recruitment (if used) -Any other documents given approval/ favorable opinion - Continuing review of trial 4 Regulatory authority(ies) To document compliance X X authorizations/ with applicable regulatory approvals/notifications where requirements (where required for: required)

- Protocol amendment(s) and other documents 6 Updates to normal To document normal values XX value(s)/range(s) for medical and ranges that are revised laboratory/technical during the trial procedure(s)/test(s) included in the protocol 7 Updates of medical/ To document that tests X X laboratory/technical remain adequate throughout procedures/tests the trial period (where required) - Certification or - Accreditation or - Established quality control and/orextemal quality assessment or - Other validation (where required) 8 Documentation of (See the section-A.15) XX investigational produces) and trial-related materialsshipment 9 Certificate(s) of analysis for (See the section-A.16) X new batches of investigational products 10 Monitoring visit reports To document site visits by, X and findings of, the monitor 11 Relevant communications To document any agreements XX other than site visits or significant discussions regarding trial administration, - Letters protocol violations, trial - Meeting notes conduct, adverse event (AE) - Notes of telephone calls reporting 12 Signed informed consent To document that consent is X forms obtained in accordance with GCP and protocol and dated prior to participation of each

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subject in trial. Also to document directaccess permission 13 Source documents To document the existence of X the subject and substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject 14 Signed, dated, and completed To document that the X X case report forms (CRFs) investigator or authorized (copy) (original) member of the investigator’s staff confirms the observations recorded 15 Documentation of CRF To document all changes/ X X corrections additions or corrections made (copy) (original) to CRF after initial data were recorded 16 Notification by originating Notification by originating XX investigator to sponsor of investigator to sponsor of serious adverse events and serious adverse events and related reports related reports in accordance 17 Notification by sponsor and/or Notification by sponsor X X investigator, where and/or investigator, where applicable, to regulatory applicable, to regulatory (where authority(ies) and authorities and IRB(s)/ required) IRB(s)/IEC(s) of unexpected IEC(s) of unexpected serious serious adverse drug adverse drug reactions and of reactions and of other safety other safety information information 18 Notification by sponsor to Notification by sponsor to XX investigators of safety investigators of safety information information 19 Interim or annual reports to Interim or annual reports XX IRB/IEC and authority(ies) provided to IRB/IEC and to (where authority(ies) required) 20 Subject screening log To document identification of XX subjects who entered pretrial (where screening required) 21 Subject identification code list To document that X investigator/ institution keeps a confidential list of names of all subjects allocated to trial numbers onenrolling in the trial. Allowsinvestigator/ institution to reveal identity of any subject 22 Subject enrollment log To document chronological X enrollment of subjects by

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trial number 23 Investigational product(s) To document that XX accountability at the site investigational products(s) have been usedaccording to the protocol 24 Signature sheet To document signatures and XX initials of all persons authorized to make entries and/or corrections on CRFs 25 Record of retained body To document location and XX fluids/tissue samples (if any) identification of retained samples if assays need to be repeated

C. After Completion or Termination of the Trial

After completion or termination of the trial, all of the documents mentioned above in section A & B should be in the file together with the following:

Title of Document Purpose Located in Files of

Investigator Sponsorlnstitution 1 Investigational To document that the XX product(s) accountability investigational at site product(s) have been used according to the protocol. To document the finalaccounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor 2 Documentation of To document destruction X X investigational of unused (if destroyed product(s) destruction investigational at site) product(s) by sponsor or at site 3 Completed subject To permit identification X identification code list of all subjects enrolled in the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upontime 4 Audit certificate (if To document that audit X required) was performed (if required) 5 Final trial close-out To document that all X monitoring report activities required for

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trial close-out are completed, and copies of essential documents are held in the appropriate files 6 Treatment allocation and Returned to sponsor to X decoding document any decoding documentation that may have occurred 7 Final report by To document X investigator/ institution completion of the trial to IRB/IEC where required, and where applicable, to the regulatory authority(ies) 8 Clinical study report To document results and X X interpretation of trial (if applicable)

Source: Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance: ICH April 1996

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ANNEXURE-VIII

GUIDANCE FOR THE INVESTIGATOR

This section should provide an overall discussion of the nonclinical and clinical data, and should summarize the information from various sources on different aspects of the investigational product(s), wherever possible. In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials. Where appropriate, the published reports on related products should be discussed. This could help the investigator to anticipate adverse drug reactions or other problems in clinical trials. The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that are based on previous human experience and on the pharmacology of the investigational product.

Investigator's Brochure (Example)

Title page-

Sponsor's Name:

Project title:

Research number:

Details of the interventions:

Release date:

Date:

Table of contents-

Confidentiality statement (Optional)

Signature page (Optional)

1. Table of contents 2. Summary

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3. Introduction 4. Physical, Chemical and Pharmaceutical properties and formulations 5. Non-clinical studies 5.1. Non-clinical Pharmacology 5.2. Pharmacokinetics and product metabolism in Animals 5.3. Toxicology 6. Effects in Human 6.1. Pharmacokinetics and product metabolism in Animals 6.2. Safety and efficacy 6.3. Marketing Experience 7. Summary of data and Guidance for the investigator References on 1. Publications 2. Reports The references should be found at the end of the chapter Appendices (if any)

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ANNEXURE-IX PROFORMA

Name Date of visit Age Registration no Sex Address Religion Marital Status Educational status Socio economic status Occupation

Presenting complaints (TOMctaHI) The main complaints with which the patient approaches the doctor. It should be mentioned with the duration.

Associated complaints (3I

H/o presenting complaints (3ie^ciPl«t>elc*

Bodily location', for pain /skin lesions/ Swelling etc. The bodily location of pain or other discomfort should be defined as accurately as possible..Patient may have more than one pain and that multiple pains may indicate multiple disease processes. Ask the patient to characterize and differentiate each.

Character: In patients own words for pain/ itching/cough/skin lesions/ discharges etc.Most patients use analogies to describe the quality of a sensation.

Spread/ radiation: The patient may be encouraged to indicate the location and spread of symptom using hand gestures, which also indicate how large an area is involved

Severity: The severity can be measured by the quantity or intensity of the symptom.The intensity of pain can be estimated on a scale of 1 to 10 or compared to another pain the patient has experienced. Other examples of quantity include volume (for example, the quantity of sputum expectorated in a day), number (for example, the number of times the patient has lost consciousness), and the degree of impairment the patient suffers. Impairment or disability is best characterized in terms of the patient's usual daily activities, such as breathlessness with climbing stairs at home or chest pain while sweeping the floor. The patient's exact words are important." Try to use the patient's own vocabulary if possible. Also can assess whether the daily routine/ Sleep/ job/ family life/ Social life (for mental disorders) etc are affected. Eg: Khalli is a similar disease as viswachi and gridhrasi but with a greater severity.

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Timing: Any pattern of appearance/ frequency/ Course/Pattern whether related to ritu kala in female etc

Relieving/Aggravating factors (3W*r:/ OTPrenn) - 3TTFTC (Food article) (Activities/regimen) (medicines) ^f?r:(Place) ehlcH:( Season/ time of the day)

Mention the specific food articles, Activities/regimen, medicines, Place, Season/ time of the day with which/ in which the complaints are relieved or aggravated. H/O past illness

A review of past medical problems and treatments not directly pertinent to the history of presenting complaints completes the past medical history. Any illness that made to visit doctor/ for a hospital stay/ to take time off the work .

Major elements of the past medical history are viz.childhood and adult illnesses, trauma, and drug sensitivities, findings in routine medical checkup etc.

(e.g prior diagnosis o f Kasa in a patient o f Rajayakshma belongs with the history o f presenting complaints, whereas a remote diagnosis o f Mutrakrichra done in the past does not)

Family history («eioicgtiia-ci:)

Medical problems in family members should be reviewed with special attention to heritable disorders.

Treatmenthistory

S Treatment •f Surgical •f Specify any adverse effects of any therapy undergone or medicine taken

This helps to assess the nidana such as Mithya upacahara/ mithya samsarjana etc in diseases and to analyse the treatment given and responses found in patient. An analysis of the previoustreatment responses of the patients gives important cluesregarding the personal featuresof the patient such as prakriti etc and state of the disease. Personal History (cl'Ufadctxjdkrl:)

It includes the daily activities of an individual which should be recorded in detail to rule out the the various faulty life styles as the nidana of the disease and to know how far the individual is deviated from healthy life style. In ayurveda , faulty life style and dietetics (mithya ahar vihar)

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are important etiological factors for most of the diseases and theindividual can be interrogated for their daily activities in a sequence they are to be observed/ pracitised daily.

Getting up in the morning: (y I d I

•S Time •S Getting up : to the alarm/ on your own after enough sleep •S Feeling after getting up: energetic/ Tired/heaviness of the body/ body ache/

The time of getting up indicate the specific dosha activity predominant in that individual. For example getting up late in the morning around 8pm ie Sleshma kala would not facilitate the routine malapravritti which is a function of vata that can easily happen in vata kala before 6 am.

Sukhena pratibodhanam ie easy waking up is a charachterstics of a healthy individual. If it does not happen , it may indicate the disease condition in the patient.

Individual if does not feel energetic, it indicate poor quality or quantity of sleep (Nidra nasha) or atinidra due to kapha vridhi.

Bath:

■S How many times:------times/ day ------times/ wk •S With hot water/ warmwater/ normal water/ cold water/ change water as per season •S Body bath alone/ head bath

If the individual does not take bath regularly, it affects the normal functioning of agni, the reproductive functioning, it can result in vitiation of rakta, sveda . It cause itching and skin diseases. Hot water is advised for body bath and if done with cold water it can result in vata/ kapha vridhi especially in vata/kapha prakriti individuals and patients with vata vyadhi.

Head bath: ...... times in a week

With hot water/ warmwater/ normal water/ cold water/change water seasonally What do you use for washing head: shampoo/ Soap/ Herbal powder

If head bath is done with hot water, it can affect the health of eyes and hair and also can cause vitiation of pitta and rakta. If done with excessivecold water, vata and kapha vitiation can happen and according to season/ disease condition, warm water can be used on head.Avoiding head bath, can result in diseases like palitya darunaka, arushika, indriya daurbalya

Time:

•S early morning/ noon/ evening v'' Before evacuating bowel/ after evacuating bowel •S Soon after exercise/ food/ heat exposure

Taking bath in the early morning after evacuation of bowels can cause agni dipti. Bathing, before evacuating the bowel can further aggravate the condition of Ajima and bathing after exercise or heat exposure can result in netra roga, sweda vaha sroto vikara, kushta etc.

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Style o f bath:

■S First water on body/ first water on head S Taken after3T3-i|§J|:/ taken without319-il3-J|: ■S Uses: Soap/ moong dal powder/ Besan ■S How body dried: Head first/ back first/ body first

Moisturizer/ Fairness cream/Coconut oil/Glycerin/Olive Oil

The results of various studies conducted to analyse the effects of long term use of moisturizers on skin suggest that long-term treatment with moisturizers on normal skin considerably reduces the skin hydration and may increase skin susceptibility to irritants.( Effect of long-term use of moisturizer on skin hydration, barrier function and susceptibility to irritants. Held E, Sveinsdottir S, Agner T.Acta Derm Venereol. 1999 Jan; 79(1):49-51.)

The results can be analysed in ayurveda as follows. The skin reflects the status of rasa dhatu and rakta dhatu in the body and the healthy skin should be mridu, snigdha, rakta vama(Unctuous skin / Smooth clear skin).Any agent that reduces the snigdhata can impart rukshataand kharata to skin causing vata vridhi which may affect the normal complexion, texture etc making it susceptible to kushta or skin diseases.

Most of the fairness creams contains topical steroids as The long-term risk associated include monomorphic acne, steroid atrophy, steroid rosacea, telangiectasia, perioral dermatitis, striae and other manifestations which have been collectively described as topical steroid damaged facies (TSDF).

This condition can be understood as the dushi visha janya vikara. These topical applications initially affect the rasa dhatu producing the various skin changes(Kotha, Mandala etc) and subsequently affect the deeper dhatus producing the other systematic manifestations.

Brushing ■S Daily once/ twice/ after every meal •S Using: Datun

Tooth paste: Sweet/ Salty/ Medicated Tooth powder/Danta manjan Cum: Salty/ Pungent/ Sweet/ medicated

It is told that Sleshma ulbana dosha cause various mukha rogas, hence it is advised to use three Rasa ie katu, tikta, kashaya which are kapha hara for danta dhavana (eventhough Susruta mention madhura rasa)(T?ra%^3^Tw^wft^^nwwTT:^«wrpra^‘)). The adjuvants mentioned are also kapka mitigating, like,kushta,tejovati chuma, (trivarga tritaya ie triphala, trikatu, triphala) are also having these rasa, honey and saindhava also useda s these does the actions like kaha chedana and kapha vilayana helping in mukha/ danta shodhana action (Ca.ka.1/15). Avoiding danta dhavana / oral hygene is specifically mentioned as a nidana of mukha roga (A.Hr.U.21/1, 2.)Daily two instances are mentioned where brushing is indicated ie every time after food and after waking up in the morning. If its not followed it can result in various tooth and oral diseases.

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Tongue Scraping: (EtcwQcflMH) Yes / no With tongue cleaner/ brush

Eventhogh modem medicine, does not stress upon the need of tongue ‘scraping’, in Ayurveda it has got greater significance as Jihva is the kapha sthana, so it should be scraped to remove the upalepa and to keep the normal character of jihva as tanu slender (Ca.Sa.8/51). In long term,it may affect the speech quality and the taste perception . The biomedical studies also show that tongue scraping gives better result than tongue brushing in removing the bacterial load and dental pique.(Winnier JJ, Rupesh S, Nayak UA, Reddy V, Prasad Rao A. The Comparative Evaluation of the Effects of Tongue Cleaning on Existing Plaque Levels in Children Jntemational Journal o f Clinical Pediatric Dentistry. 2013; 6(3): 188- 192. Doi: 10.5005/jp-joumals-10005-1216.)

Any habit o f applying medicated 3J5Z5firT? Any habit o f applying oil on nostrils ( in IcfiJznft):-----times/week:-----times/ month Any habit o f — times in a week/----- times in a month Any habit o f cfTZWoT: — times in a week/-----times in a month Ingredients used: Paan/ Supari/ Any habit o f taking WT:

Oil Application:3T3-^s<< I: Applying oil: Head daily/— times in a week/-----times in a month Ear daily/— times in a week/-----times in a month Soles daily/— times in a week/-----times in a month Limbs daily/— times in a week/-----times in a month Whole body daily/— times in a week/-----times in a month Oil used: Gingely oil/ Mustard oil/ Coconut oil/ Olive oil/ medicated/Any other oil 3T3-^s<»i: After food/ without bowel evacuation/ after bath Any adverse reaction after using any specific oil for3T3-^s-<*i:? o«ii

Diet and Food habits (3iig>K) 1. How many times you eat in a day (Major Meal)? Thrice Daily/ Less than three times /Frequently/ varying, not constant

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2. What kind of food you usually take? Heavy food / Light food/ Mixed, not specific 3. How do you rate your food quantity? Normal as compared to your peers /less always /Excess always/ Sometimes excess sometimes less- 4. Do you get hunger for the successive food time? Yes /No /Gets hunger before food time /Sometimes yes sometimes no 5. How do you enjoy the taste of food? Generally enjoy the taste during food time Appreciate the taste any time generally Usually not / sometimes yes sometimes no- 6. If at all indigestion happens, what kind of symptoms you get? Relieves with mild disturbances Heaviness, Salivation, Swelling of eyelids, Taste of food in eructation Giddiness, Thirst, Sourbelching,Burning sensation Abdominal colic,Distension of abdomen, Constipation 7. How is your indigestion usually relieved? With skipping 1-2 meals/ within 2-3 days with medicine/ By skipping 1 meal Varies every time 8. What is the nature of eructation you get? Clear With the taste of food taken/Buming sensation/Sour Pungent,rarely occurs. No Specific taste,But frequently occur with abdominal colic 9. How do you feel when you skip the meal? Can’t skip the meal, if skips with mild disturbances Usually Skips the meal Can’t skip the meal, troubles with headache,nausea,low energy, difficulty to concentrateetc Sometimes can skip the meal and sometimes cannot 10. What is the pattern of your digestion? Usually digest the food taken Takes longer time to digest even the wholesome food Digest even the incompatible food immediately

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Sometimes digest the food and sometimes not 11. Which taste you usually prefer in your diet? Not specific, likes to include all taste/Hot,Spicy,Sour/Sweet/It varies Routinely consumed food Time Ingredient Quantity Liquid Mom breakfast Lunch Eve snacks Dinner Any Other

•S Type of diet: Veg/ Non veg ■S Vegetarian: • Grain: Rice/ Wheat/ Ragi/Jowar/Barley/Any other • Pulses: Green gram/ black gram/ Horse gram/Bengal gram/Any other S Non Vegetarian • Regular/ Irregular • Once in a wk/ fortnight/ month/rare • Type: egg/ Chicken/ Mutton/ beef/ Pork/Any other Habit of taking stale food? Any sudden change in your routine food habits/ articles?

Drinking Water S Source : Tap Water ( Filtered/ Non Filtered) / Ground water S Type : Cold/ Chilled / Boiled and Cooled/ Medicated ■S Quantity: How many glasses per day/ night? •S Habit of drinking large amount of water soon after waking up? ■S Habit of drinking water and vomiting out on empty stomach each day?

v'' Dominant rasa:to be assessed by physician •S Dominant dJ|uI:to be assessed by physician •S Dietary habits: 3W3W/ Jf^RToT/ fcHtm^M/ hPIcII^Iti/ 3^T3W S involved: to be assessed by analyzing the food habits

(place) 3lei^ira*c\tr (State of health) «hM^4?<^6T sb

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(quantity) (treatment)

(wholesome) MIchT^'bc^T (cooking)

(combination)

(mode of preparation)

(potency) -HMdJcHdiU (richness of quality)

(rules for eating)

cR^ifcH?d;tr— fish + milk

— heated honey. Deep frying vegetables, Reheating oil and food

— honey + cow’s ghee mixed in equal proportion.

sh-H^'tdiU— hot water after taking honey.

cbM^'bc\tr— pungent substance in summer and cold substances in winter.

— consuming cold water immediately after having hot tea or coffee.

Banana+ milk Curd+ Milk+Rice Fruit Salad Butter milk+ Milk+Rice Milk Shake Moong Khichdi+Milk Milk +Rice+ Salt Mi1k+ Fish Curd at night Plain Curd Heated/ boiled curd Refrigerated water after hot meal Excessive water after taking meal Cold/ Refrigerated water after snigdha ahara Non veg food with honey/ milk/ black gram/ Sweet and sour fruits in a fruit chat

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(Bowel evacuation:) •S Feeling of urge: Soon after waking up After sometime without supplementation After taking food/ liquid/ Solid After medication Varying/Other Urge to evaculate immediately after or during a meal ■S Frequency:- Daily------times;------times/week After every meal ■S Time required:------minutes (time taken) S Consistency: Pellets like very hard/ hard/ Banana like/ Semi solid/ watery/ Varying S Symptoms associated with evacuation: pain/ ciiciyqjrl/ burning sensation/itching •S Mixed with mucous: yes/ no/sometimes (mention the frequency) •S Mixed with blood yes/ no/ sometimes (mention the frequency) •S Presence of undigested material: yes/ no/ sometimes (mention the frequency) •f H/O worms/ presence of worms: yes/ no ■S Frequency of worm infestation: -times/ 6months S Evacuation: Complete/ Incomplete/Unsatisfactory/ varying ■S Color of stool: ■S Odour of stool: •S Quantity of stool: ■S Habit of suppressing the urge/ initiating the urge

It is very difficult to assess the nature of agni with from the nature of bowel habits. The following references were helpful to draw important conclusions.Sabhakta sanna annapTDita purTUa, (faeces mixed with food articles) were found inpurTUavUta vata kopa1, amajatisara , grahaUi3 etc. Faeces mixed with mucous is found in kaphdvUta apdna vata kopa4, kaphaja atTsara5, kaphaja grahaUf, kaphaja arsa1 etc.Unformed faeces (asamhata, sithila) are formed in snehana samyak yogasand kaphaja arias9.Hard faeces is found in vata vDddhi10, vdtaja atTsdra, uddvarta, vatikajvara, vatika arsas etc.Dry faeces (suska) are found in vitavrta vata kopa, vataja atTsara, vatika grahani, vatika gulma, udavarta etc.Faeces in excessive quantity are found in pitta prakrti, kardama visarpa, kaphaja arsa etc.

lCa.Ci.28/71 2Su.U. 40/16 *A.Hn.Ni.8/27 4 Ca. Ci. 28/3 3 5Ca.Ci.l9/7 6Ca.Ci.l5/17 1 Ma.Ni.5/23 *Ca.Sii. 13/58 9 Ca.Ci. 14/173 10 Su.Su. 15/31

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Scanty faeces (alpa) is found in vataja grahaUi, vdtaja udavarta, pa \u, vataja arsas etc. (Micturition) v'' Frequency: -----times/day; -----times/ night •S Colour: White/yellowish/Yellow/turbid/Reddish •S Associated symptoms: Painful/ burning sensation/ Itching/ Scanty/Incomplete voiding/ Urgency/incomplete voiding/ Crystals in urine/ Semen with urine

(sweating) •S Sweating More sweat throught the year/ Summer season/ After physical exercise Compared to others: Excess/ Similar/Less •f Odour: Excess/ Moderate/ Irregular/Nil S Stain on clothes: Y/N S Stains clear after washing Yes/No ■S Sweat especially on soles of palmand feet yes/No fStjtT: Sleep ■/ -----Hrs/ night Sound sleep/ Disturbed/ Reduced v'' How many times do you wake up in the middle of the night v'' How much time does it take to go back to sleep ■S How time does it take to fall asleep after you get into bed at bedtime ■S If disturbed:- (In initiation/ In middle/ end part of sleep) ■S Day time job/ night Shifts ■/ ------Hrs/ day After lunch ■ Before food •S Dream habits: Excess/ Moderate/ Less •S Other complaints: Biting teeth/ Bed wetting/ sleep talking/ sleep walking

(o«i vi Addiction

S.No Addiction No.of times/day:/ Quantity Since:----- Months/ Years 1. Smoking 2. Alcohol 3. Pan/Gutka 4. Tea/Coffee 5. Mobile Phone/ Computer/ Hours spent in a day: Social Media 6. Others

92 General Guidelines for Clinical Evaluation of Ayurvedic Interventions ■Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

(Menstrual history) S Menarche Age •S Regular/Irregular •S Interval: •S Flow — Pads/day; Duration------days S Amount: Average/ Scanty/ heavy S Colour: v'' Consistency: thin/thick ^ Clots: Excessive/moderate/Nil ■S Stains on washing: Yes/No ■S Foul smell: •S Other complaints: During/ Pre/Post S H/O any related medication/Contraceptives •S Date of last menstrual period: •S Menopausal Age: (Sex and Marital history) ^ Age of marriage •f Relationship with the spouse ■S Family planning Children boys/Girls S Any H/O disease to the spouse: Obstetrical history(« *1 q ejd i«-ci:) •S Gravida •S Para •S Abortion •f Live birth/ Dead :- Female— Male----- ■f Mode of delivery: FTND/Preterm ND ■S Forceps/ ventous ✓ C.S ■S Abortion: Spontaneous/ Induced ■S Last Delivery ■S Last Abortion ■S Have you followed? S Garbhini paricarya, Yes/ No, If yes give details ■S Sutika paricarya Yes/ No, If yes give details •S Paricharya after abortion: Yes/ No, If yes give details

Occupational history(°±l IM FJHtI W:) S Type of job: Sedentary/ exhausting/Intellectual/Mental stress/ Ac/Hot/ Night Shifts/Computer work/Typing/ Teaching/ Police professional ^ Work place: ■S Posture while working:

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 93 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

•S Working Hours: •f Travel:---- km/day Conveyance:- S Attitude towards the job ■S Relationship at work place ■S Punishments if any S Are you satisfied with your job? If not, what are the reasons?

In the order of cj*W W?*T) 1. 3T5?T7T

2. 3. 4. ^ 5.

I. 31f3FltrSfTT

313J|.h£

cht®d

'•■elc; W *te=2T chU^ cHIUcI

3TT^TTT

chJ- m i

* l c l h t a

1. Check for clld/f^W/ <+>41 H'l'd vitiating 3TT^R/I^^K 2. ^r&giB^r-prsfTw 3. (A.San.Su.19) 4. ^TcT-oRfTUT (A.San.Su.19) 5. ?TW-Pl<.l

6. Involvement of 3 i i c k u i ( Ca.Ci.28)

94 General Guidelines for Clinical Evaluation of Ayurvedic Interventions ■Illlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

(*IT

2. 3. VK^Hol-pTffTW

<9 i. 2. ?TR 3. 4.

IfW^T, 1. 3=TT^5T 2. f^cJST

s f^rsr /3HMI0-HJ If f^t5T, If 3HNIo-el«3 1. 3TTTTTCRT l,?l

2. Hct"C|RI'i| 2, vJla-ciqicI

v' ?TTfR/ JTTSW/^TTtfT-JTRTCT v' 3q^h5T/

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 95 Illllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

•S c{l°lvjl/ both

(Enlist and analyze from history and examination) 1. f^SfloT

2. Hci^H<\ 3. 4. 3^RRT

2 . 3.

4. 'fei'ld'l^i^C.-VlchK 5. 3iRoi

6. chl^o 7. Involvement of3TW 8. 3s^ra‘-^rra‘ 9. ^TR-^JT^T 10. cA|ct-d-^JW

11. '0 JI

12. 1sh4|chM 13. c3TTl^3ra^8TT

14. 'Cld|y«+>fc1 15. 3 ^

♦xiq^Aci^-PleiW (Differential diagnosis) o2TTf^rf%fat?^Rr:(Final Diagnosis)

96 General Guidelines for Clinical Evaluation of Ayurvedic Interventions 1 IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I IN I I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I IN I I IN I I IN I I III I IN I I IN I I IN I I III I IN I

ANNEXURE-X

EXPERTS INVOLVED IN DEVELOPMENT OF GUIDELINES AND CONSULTATIVE PROCESS

Working group

1. Vd. (Prof.) K. S. Dhiman Director General | Central Council for Research in Ayurvedic Sciences | New Delhi 2. Dr. N.Srikanth Deputy Director General | Central Council for Research in Ayurvedic Sciences | New Delhi 3. Dr. Bharti Assistant Director (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 4. Dr.B.C.S.Rao Assistant Director (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 5. Dr. Sarada Ota Research Officer (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 6. Dr. Sunita Research Officer (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 7. Dr. Shruti Khanduri Research Officer (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 8. Dr. Babita Yadav Research Officer (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 9. Dr. Renu Singh Research Officer (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi 10. Dr. Kishore Kumar Research Officer (Ayu.)|Regional Ayurveda Research Institute for Metabolic Disorders! Bengaluru 11. Dr. Sakshi Sharma Research Officer (Ayu.)| Central Ayurveda Research Institute for Cardiovascular Diseases | New Delhi

Members of National Consultation

Technical Assistance

1. Dr. Aarti Sheetal Senior Research Fellow (Ayu.) | Central Council for Research in Ayurvedic Sciences | New Delhi

General Guidelines for Clinical Evaluation of Ayurvedic Interventions 97

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